Nitropyridine compound

ABSTRACT

This invention provides 5-HT1F agonists of Formula I: where A-B, X, and R are as defined in the specification. The invention also encompasses pharmaceutical formulations employing compounds of Formula I as well as methods of treating conditions associated with 5-HT1F activation employing these compounds or compositions. The invention also provides intermediates useful for the preparation of the compounds of Formula I.

CROSS-REFERENCE

This application is a divisional of application Ser. No. 08/969,851,filed Nov. 14, 1997, which claims the benefit of U.S. ProvisionalApplication No. 60/030,950, filed Nov. 15, 1996.

BACKGROUND OF THE INVENTION

Serotonin (5-HT) exhibits diverse physiological activity mediated by atleast seven receptor classes, the most heterogeneous of which appears tobe 5-HT₁. A human gene which expresses one of these 5-HT₁ receptorsubtypes, named 5-HT_(1F), was isolated by Kao and coworkers (Proc.Natl. Acad. Sci. USA, 90, 408-412 (1993)). This 5-HT_(1F) receptorexhibits a pharmacological profile distinct from any serotonergicreceptor yet described.

Moskowitz has proposed that currently unknown triggers for painstimulate trigeminal ganglia which innervate vasculature within thecephalic tissue, giving rise to release of vasoactive neuropeptides fromaxons on the vasculature. These released neuropeptides then activate aseries of events, a consequence of which is pain. This neurogenicinflammation is blocked by sumatriptan and ergot alkaloids by mechanismsinvolving 5-HT receptors, believed to be closely related to the5-HT_(1D) subtype, located on the trigeminovascular fibers (Neurology,43(suppl. 3), S16-S20 (1993)). It has been demonstrated that agonists ofthe 5-HT_(1F) receptor inhibit peptide extravasation due to stimulationof the trigeminal ganglia (Audia and Nissen, U.S. Pat. No. 5,521,196).

Compounds which exhibit affinity for the 5-HT_(1F) receptor provide anew approach for the treatment of diseases linked to abnormalserotonergic neurotransmission. Furthermore, compounds selective for the5-HT_(1F) receptor subtype are potentially useful for treating suchdiseases while causing fewer undesired side effects.

SUMMARY OF THE INVENTION

The present invention provides 5-substituted-3-(piperidin-4-yl)- and5-substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridinesof Formula I: ##STR2## in which A--B is --C═CH-- or --CH--CH₂ --;

R is H, C₁ -C₆ alkyl, benzyl, or phenylethyl;

X is --NR¹ SO₂ R², --NHC(Q)NR³ R⁴, --NHC(O)OR⁵, or --NR¹ C(O)R⁶ where:

Q is O, or S;

R¹ is H or C₁ -C₄ alkyl;

R² is C₁ -C₄ alkyl, phenyl or substituted phenyl;

R³ and R⁴ are independently selected from the group consisting of H, C₁-C₆ alkyl, C₃ -C₆ alkenyl, C₃ -C₈ cycloalkyl, phenyl, substitutedphenyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄ alkylenyl) substituted inthe phenyl ring, ((C₁ -C₄ alkyl or C₁ -C₄ alkoxycarbonyl substituted)C₁-C₄ alkyl)phenyl, C₁ -C₄ alkyl α-substituted with C₁ -C₄ alkoxycarbonyl,heteroaryl; or

R³ and R⁴ taken together with the nitrogen atom to which they areattached form a pyrrolidine, piperidine, piperazine, 4-substitutedpiperazine, morpholine or thiomorpholine ring;

R⁵ is C₁ -C₆ alkyl, C₃ -C₆ alkenyl, phenyl, substituted phenyl, C₃ -C₈cycloalkyl, C₁ -C₄ alkyl ω-substituted with C₁ -C₄ alkoxy;

R⁶ is C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀alkynyl, C₃ -C₈ cycloalkyl, phenyl, substituted phenyl, naphthyl,phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄ alkylene) substituted on thephenyl ring, 2-phenylethylen-1-yl, diphenylmethyl, benzofused C₄ -C₈cycloalkyl, C₁ -C₄ alkylene ω-substituted with C₃ -C₆ cycloalkyl, or aheterocycle; and pharmaceutically acceptable acid addition salts andsolvates thereof.

This invention also provides a pharmaceutical formulation whichcomprises, in association with a pharmaceutically acceptable carrier,diluent or excipient, a compound of Formula I.

A further embodiment of this invention is a method for increasingactivation of the 5-HT_(1F) receptor for treating a variety of disorderswhich have been linked to decreased neurotransmission of serotonin inmammals. Included among these disorders are depression, migraine pain,bulimia, premenstrual syndrome or late luteal phase syndrome,alcoholism, tobacco abuse, panic disorder, anxiety, general pain,chronic pain, post-traumatic syndrome, memory loss, dementia of aging,social phobia, attention deficit hyperactivity disorder, disruptivebehavior disorders, impulse control disorders, borderline personalitydisorder, obsessive compulsive disorder, chronic fatigue syndrome,premature ejaculation, erectile difficulty, anorexia nervosa, disordersof sleep, autism, mutism, allergic rhinitis, trichotillomania,trigeminal neuralgia, dental pain or temperomandibular joint dysfunctionpain. The compounds of this invention are also useful as a prophylactictreatment for migraine. Any of these methods employ a compound ofFormula I.

The use of a compound of Formula I for the activation of the 5-HT_(1F)receptor, for the inhibition of peptide extravasation in general or dueto stimulation of the trigeminal ganglia specifically, and for thetreatment of any of the disorders described supra, are all embodimentsof the present invention.

The present invention also includes intermediates useful for thepreparation of compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The general chemical terms used in the formulae above have their usualmeanings. For example, the term "alkyl" includes such groups as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, 2-pent-yl-, 3-pentyl-, neopentyl, hexyl, heptyl, octyl and thelike. The term "alkoxy" includes such groups as methoxy, ethoxy,isopropoxy, sec-butoxy, tert-butoxy, 2-pentoxy-, 3-hexyloxy, heptyloxy,octyloxy, and the like. The term "alkylthio" includes such groups asmethylthio, ethylthio, isopropylthio, sec-butylthio, tert-butylthio, andthe like. The term "alkenyl" includes vinyl, allyl, 1-buten-4-yl,2-buten-4-yl, 1-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl, 1-hexen-6-yl,2-hexen-6-yl, 3-hexen-6-yl, 4-hexen-6-yl and the like. The term"alkyny", includes acetylenyl, propynyl, 2-butyn-4-yl, 1-butyn-4-yl,1-pentyn-5-yl, 2-pentyn-5-yl and the like. The term "acyl" includes, forexample, formyl, acetyl, propanoyl, butanoyl, and 2-methylpropanoyl. Theterm "cycloalky" includes such groups as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cycloocryl. The term "phenyl(C₁-C₄ alkylene)" includes such groups as benzyl, phenethyl, phenpropyl andphenbutyl. The term "(C₁ -C₄ alkyl)sulfony" includes methanesulfonyl,ethanesulfonyl propanesulfonyl, isopropanesulfonyl, butanesulfonyl andthe like. The term "halo" includes fluoro, chloro, bromo and iodo.

The term "substituted alkyl" is taken to mean an alkyl moietysubstituted with up to three substituents selected from the groupconsisting of hydroxy, C₁ -C₄ alkoxy, halo, aryloxy, C₁ -C₄alkoxycarbonyl and heteroaryloxy.

The term "substituted phenyl" or "phenyl(C₁ -C₄ alkylene) substituted inthe phenyl ring" is taken to mean the phenyl moiety may be substitutedwith one substituent selected from the group consisting of halo, C₁ -C₄alkyl, C₁ -C₈ alkoxy, C₁ -C₄ alkylthio, nitro, cyano, di(C₁ -C₄alkyl)amino, trifluoromethyl, trifluoromethoxy, phenyl, C₁ -C₄ acyl,benzoyl or (C₁ -C₄ alkyl)sulfonyl, or two to three substituentsindependently selected from the group consisting of halo, nitro, C₁ -C₄alkyl, or C₁ -C₄ alkoxy.

The term "heterocycle" is taken to mean stable aromatic and non-aromatic5- and 6-membered rings containing carbon and from 1 to 3 heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur, saidrings being optionally monobenzofused. All of these rings may besubstituted with up to three substituents independently selected fromthe group consisting of halo, C₁ -C₄ alkoxy, C₁ -C₄ alkyl, cyano, nitro,hydroxy, --S(O)_(n) --(C₁ -C₄ alkyl) and --S(O)_(n) -phenyl where n is0, 1 or 2. Where tautomers are possible, all tautomeric forms arecontemplated by the present invention. Non-aromatic rings include, forexample, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl,oxazolidinyl, dioxanyl, pyranyl, and the like. Benzofused non-aromaticrings include indolinyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl and the like. Aromatic rings includefuryl, thienyl, pyridinyl, pyridinyl-N-oxide, pyrrolyl,N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl,pyridazinyl, and the like. Benzofused aromatic rings includeisoquinolinyl, isoquinolinyl-N-oxide, benzoxazolyl, benzthiazolyl,quinolinyl, quinolinyl-N-oxide, benzofuranyl, thionaphthyl, indolyl andthe like.

The term "heteroaryl" is taken to mean an aromatic or benzofusedaromatic heterocycle as defined in the previous paragraph. The term"substituted heteroaryl" is taken to mean an aromatic or benzofusedaromatic heterocycle as defined in the previous paragraph substitutedwith up to three substituents independently selected from the groupconsisting of halo, C₁ -C₄ alkoxy, C₁ -C₄ alkyl, cyano, nitro, hydroxy,--S(O)_(n) --(C₁ -C₄ alkyl) and --S(O)_(n) -phenyl where n is 0, 1 or 2.Where tautomers are possible, all tautomeric forms are contemplated bythe present invention. The term heteroaryl(C₁ -C₄ alkyl) is taken tomean a branched or linear alkyl chain of 1 to 4 carbon atoms substitutedat some point with an aromatic or benzofused aromatic heterocyclemoiety. The term "substituted heteroaryl(C₁ -C₄ alkyl)" is taken to meana branched or linear alkyl chain of 1 to 4 carbon atoms substituted atsome point with an aromatic or benzofused aromatic heterocycle moietywhich is substituted with up to three substituents independentlyselected from the group consisting of halo, C₁ -C₄ alkoxy, C₁ -C₄ alkyl,cyano, nitro, hydroxy, --S(O)_(n) --(C₁ -C₄ alkyl) and --S(O)_(n)-phenyl where n is 0, 1 or 2.

The term "heteroaryloxy" is taken to mean a heteroaryl or substitutedheteroaryl group, as defined in the previous paragraph, bonded to anoxygen atom.

The term "aryloxy" is taken to mean a phenyl or substituted phenyl groupbonded to an oxygen atom.

The term "4-substituted piperazine" is taken to mean a piperazine ringsubstituted at the 4-position with a substituent selected from the groupconsisting of C₁ -C₆ alkyl, C₁ -C₄ alkoxy substituted C₁ -C₆ alkyl,phenyl, substituted phenyl, phenyl(C₁ -C₄ alkylene), phenyl(C₁ -C₄alkylene) substituted in the phenyl ring, heteroaryl, and heteroaryl(C₁-C₄ alkylene).

The term "benzofused C₄ -C₈ cycloalkyl" is taken to mean a C₄ -C₈cycloalkyl group fused to a phenyl ring. Examples of these groupsinclude benzocyclobutyl, indanyl, 1,2,3,4-tetrahydronaphthyl, and thelike.

While all of the compounds of this invention are useful as 5-HT_(1F)agonists, certain classes are preferred. The following paragraphsdescribe such preferred classes.

aa) R is hydrogen;

ab) R is methyl;

ac) X is --NR¹ SO₂ R² ;

ad) X is --NHC(Q)NR³ R⁴ ;

ae) X is --NHC(O)OR⁵ ;

af) X is --NR¹ C(O)R⁶ ;

ag) Q is O;

ah) R¹ is H;

ai) R² is phenyl;

aj) R³ is H;

ak) R⁴ is C₁ -C₄ alkyl;

al) R⁴ is methyl;

am) R⁴ is phenyl;

an) R⁴ is C₃ -C₈ alkenyl;

ao) R⁴ is allyl;

ap) R⁴ is phenyl monosubstituted with halo;

aq) R⁴ is 4-fluorophenyl;

ar) R⁴ is heteroaryl;

as) R⁴ is 4-pyridyl;

at) R⁵ is C₁ -C₄ alkyl;

au) R⁵ is methyl;

av) R⁵ is ethyl;

aw) R⁵ is propyl;

ax) R⁶ is C₁ -C₁₀ alkyl;

ay) R⁶ is C₁ -C₄ alkyl;

az) R⁶ is methyl;

ba) R⁶ is ethyl;

bb) R⁶ is propyl;

bc) R⁶ is C₃ -C₆ alkenyl;

bd) R⁶ is allyl;

be) R⁶ is C₃ -C₆ cycloalkyl;

bf) R⁶ is cyclopropyl;

bg) R⁶ is cyclobutyl;

bd) R⁶ is phenyl;

be) R⁶ is phenyl monosubstituted with halo;

bf) R⁶ is phenyl monosubstituted with fluoro;

bg) R⁶ is 4-fluorophenyl;

bh) R⁶ is phenyl monosubstituted with nitro;

bi) R⁶ is phenyl monosubstituted with cyano;

bj) R⁶ is 4-nitrophenyl;

bk) R⁶ is 4-cyanophenyl;

bl) R⁶ is a heterocycle;

bm) R⁶ is furyl optionally substituted with C₁ -C₄ alkyl, C₁ -C₄ alkoxy,or halo;

bn) R⁶ is 3-furyl;

bo) R⁶ is thienyl optionally substituted with halo, C₁ -C₄ alkyl or C₁-C₄ alkoxy;

bp) R⁶ is 3-thienyl;

bq) R⁶ is pyridinyl optionally substituted with halo, C₁ -C₄ alkyl or C₁-C₄ alkoxy;

br) R⁶ is 4-pyridinyl;

bs) A--B is --C═CH--;

bt) A--B is --CH--CH₂ --;

bu) The compound is a free base;

bv) The compound is a salt;

bw) The compound is the hydrochloride salt;

bx) The compound is the fumarate salt.

It will be understood that the above classes may be combined to formadditional preferred classes.

The compounds of the present invention may, depending upon theirstructure and manner of synthesis and isolation, exist as apharmaceutically acceptable solvate. These solvates include water,methanol, and ethanol. Solvated forms of the compounds of the presentinvention represent a further embodiment of the present invention.

The compounds of this invention are useful in a method for increasingactivation of the 5-HT_(1F) receptor for treating a variety of disorderswhich have been linked to decreased neurotransmission of serotonin inmammals. It is preferred that the mammal to be treated by theadministration of compounds of this invention is human.

Since the compounds of this invention are amines, they are basic innature and accordingly react with any of a number of inorganic andorganic acids to form pharmaceutically acceptable acid addition salts.It is preferable to convert the free amines to their pharmaceuticallyacceptable acid addition salts for ease of handling and administration.Acids commonly employed to form such salts are inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,phosphoric acid, and the like, and organic acids, such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid or fumaric acid.

The following group is illustrative of compounds contemplated within thescope of this invention:

N-propyl-N'-(3-(1-(2-pentyl)-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea decanoate

N-butyl-N'-(3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea acrylate

N-(2-methoxy)phenyl-N'-(3-(1-(sec-butyl)-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea formate

N-(4-propoxy)phenyl-N'-(3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea isobutyrate

N-(2-butoxy)phenyl-N'-(3-(1-hexylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea fumarate

N-(2,3-dibromo)phenyl -N'-(3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea caproate

N-(2-bromo-3-iodo)phenyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea heptanoate

N-(3-phenpropyl)-N'-(3-(1-(sec-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea propiolate

N-(4-trifluoromethyl)phenyl-N'-(3-(1-neopentyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea oxalate

N-(4-phenyl)phenyl-N'-(3-(1-pentylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)thiourea malonate

N-hexyl-N'-(3-(1-propylpiperidin-4-yl)pyrrolo 3,2-b!pyridin-5-yl)ureasuccinate

N-(2-buten-4-yl)-N'-(3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea suberate

N-(3-hexen-6-yl)-N'-(3(1-(3-pentyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea sebacate

N-cyclopropyl-N'-(3-(1-hexyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea fumarate

N-cyclopentyl-N'-(3-(1-(3-pentyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea maleate

N-cyclooctyl-N,-(3-(1-(tert-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea malonate

N-(2-chloro)phenyl-N'-(3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea mandelate

N-(3-phenyl)phenyl-N'-(3-(1-propyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea butyne-1,4-dioate

N-(2-ethoxy)phenyl-N'-(3-(1-neopentylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea hexyne-1,6-dioate

N-(4-isopropoxy)phenyl-N'-(3-(1-isobutylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea benzoate

N-(2-formyl)phenyl-N'-(3-(1-(3-pentyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea 4-chlorobenzoate

N-(3-propanoyl)phenyl-N'-(3-(1-pentylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea 2-methylbenzoate

N-(3-ethylthio)phenyl-N'-(3-(1-propylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea 2,4-dinitrobenzoate

N-(3-isopropylthio)phenyl-N'-(3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea 3-hydroxybenzoate

N-(2-methyl)phenyl-N'-(3-(1-propylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea 4-methoxybenzoate

N-(3-isopropyl)phenyl-N'-(3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea phthalate

N-(2-ethoxycarbonyl)phenyl-N'-(3-(1-(tert-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea sulfonate

N-(2-butoxycarbonyl)phenyl-N'-(3-(1-propylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

N-(3,4-difluoro)phenyl-N'-(3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

N-(3-chloro-4-bromo)phenyl-N'-(3-(1-(3-pentyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

N-(3-phenpropyl)-N'-(3-(1-propylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

N-ethyl-N-phenyl-N,-(3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

N-isopropyl-N-phenyl-N'-(3-(1-(sec-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

N-ethyl-N-methyl-N'-(3-(1-(2-pentyl)piperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

N-methyl-N-isopropyl-N'-(3-(1-neopentylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

N,N-diisopropyl-N'-(3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl)urea

5-butoxycarbonylamino-3-(1-propyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

5-(2-buten-4-yloxy)carbonylamino-3-(-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

5-(2-penten-5-yloxy)carbonylamino-3-(1-(sec-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridine

5-(3-chlorophenoxy)carbonylamino-3-(1-hexylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-methoxyphenoxy)carbonylamino-3-(1-hexylpiperidin-4-yl) -2-pyrrolo3,2-b!pyridine citrate

5-(3-butoxyphenoxy)carbonylamino-3-(1-neopentylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-cyclopropoxycarbonylamino-3-(1-(tert-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridine

5-cyclohexyloxycarbonylamino-3-(1-isobutylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-cyclooctyloxycarbonylamino-3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(propoxyethoxy)carbonylamino-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(4-methoxybutoxy)carbonylamino(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(propanoyl)amino-3-(1-neopentylpiperidin-4-yl)pyrrolo 3,2-b!pyridinemandelate

5-(2-methylpropanoyl)amino-3-(1-(3-pentyl)piperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-methyl-4-butyn-1-oyl)amino-3-(1-(tert-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-methylbutanoyl)-N-methylamino-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine phenylacetate

5-(hex-3-enoyl)amino-3-(1-propylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

5-(cyclohexaneacetyl)amino-3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(cycloheptylcarbonyl)amino-3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridine phenylpropionate

5-(4-phenyibutanoyl)amino-3-(1-isopropyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine phenylbutyrate

5-(5-phenoxypentanoyl)amino-3-(1-neopentyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine citrate

5-(5-methoxypentanoyl)amino-3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridine lactate

5-((3-propoxycarbonyl)propanoyl)amino-3-(1-isobutylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-((5-methoxycarbonyl)pentanoyl)amino-3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridineβ-hydroxybutyrate

5-(benzoyl-N-ethyl)amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridineglycollate

5-benzoylamino-3-(1-propylpiperidin-4-yl)pyrrolo 3,2-b!pyridine tartrate

5-benzoylaimino-3-(1-isopropylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

5-benzoylamino-3-(1-(tert-butyl)-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine hydrochloride

5-(4-fluorobenzoyl)amino-3-(1-ethyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

5-(4-(formyl)benzoyl)amino-3-(1-(sec-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridine

5-(3-(butanoyl)benzoyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-(butanoyl)benzoyl)amino-3-(1-neopentylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-(benzoyl)benzoyl)amino-3-(1-pentylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-(methanesulfonyl)benzoyl)amino-3-(1-butylpiperidin-4-yl)pyrrolo3,2-blpyridine

5-(3-phenylbenzoyl)amino-3-(1-(tert-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2,3-dibromo)benzoyl-N-isopropylamino-3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-bromo-3-iodo)benzoylamino-3-(1-(2-pentyl)piperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-thiophenecarbonyl)-N-butylamino-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-thiophenecarbonyl)amino-3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-thiophenecarbonyl)amino-3-(1-(tert-butyl)piperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-thiophenecarbonyl)amino-3-(1-hexylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(3-thiophenecarbonyl)amino-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-furoyl)amino-3-(1-isopropyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

5-(2-furoyl)amino-3-(1-butyl-1,2,3,4-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

5-(2-furoyl)amino-3-(1-neopentylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

5-(3-furoyl)amino-3-(1-butylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

5-(2-pyridinecarbonyl)amino-3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-chloro-4-pyridinecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(3-pyrrolecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-oxazolecarbonyl)amino-3-(1-hexylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-methyl-4-oxazolecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(4-pyrazolecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(5-isoxazolecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(3-imidazolecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-methoxy-4-pyrimidinecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-quinolinecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

5-(2-cyano-5-quinolinecarbonyl)amino-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

The compounds of this invention are prepared by reacting an appropriate5-aminopyrrolo 3,2-b!pyridine of formula II with a suitable electrophileby methods well known to one of ordinary skill in the art. Thischemistry is described in Synthetic Scheme I where R' is C₁ -C₄ alkyl,(C₁ -C₄ alkoxy)carbonyl, benzyl, or phenylethyl, and A--B and R¹ -R⁶ areas previously defined. ##STR3##

The compounds of the invention where X is --NR¹ SO₂ R² may be preparedby reacting a 5-amninopyrrolo 3,2-b!pyridine with an appropriatesulfonyl halide or anhydride to give the corresponding sulfonamide. Asolution of the 5-aminopyrrolo 3,2-b!pyridine in a suitable solvent,such as pyridine, tetrahydrofuran, dioxane, diethyl ether ordimethylformamide, at a temperature from about ambient to about 0° C.,is reacted with a commercially available R² -sulfonyl halide or R²-sulfonic anhydride in the presence of a suitable base such as pyridineor triethylamine. The resultant sulfonamide is isolated by normalextractive workup and the product purified by chromatography, or byrecrystallization from a suitable solvent. The skilled artisan willappreciate that when pyridine is used as solvent, no additional base isrequired.

Compounds of the invention where X is --NHC(Q)NR³ R⁴ are prepared bytreating a solution of the 5-aminopyrrolo 3,2-b!pyridine in a suitablesolvent, such as tetrahydrofuran, dimethylformamide, chloroform ordichloromethane, with an appropriate isocyanate, isothiocyanate,carbamoyl chloride or carbamoyl bromide. Appropriate carbamoyl chloridesare available by treating an amine of formula HNR³ R⁴ with phosgene.When a carbamoyl chloride or carbamoyl bromide is used, the reactionsare performed in the presence of a suitable base. Suitable bases includeamines typically used as acid scavengers, such as pyridine ortriethylamine, or commercially available polymer bound bases such aspolyvinylpyridine. If necessary, an excess of the isocyanate,isothiocyanate, carbamoyl chloride or carbamoyl bromide is employed toensure complete reaction of the starting amine. The reactions areperformed at about ambient to about 80° C., for from about three hoursto about three days. Typically, the product may be isolated by washingthe reaction mixture with water and concentrating the remaining organicsunder reduced pressure. When an excess of isocyanate, isothiocyanate,carbamoyl chloride or carbamoyl bromide has been used, however, apolymer bound primary or secondary amine, such as an aminomethylatedpolystyrene, may be conveniently added to react with the excess reagent.Isolation of products from reactions where a polymer bound reagent hasbeen used is greatly simplified, requiring only filtration of thereaction mixture and then concentration of the filtrate under reducedpressure. The product from these reactions may be purifiedchromatographically or recrystallized from a suitable solvent ifdesired. The skilled artisan will appreciate that compounds of theinvention which are ureas may be converted into the correspondingthiourea by treatment with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide!(Lawesson's Reagent) or phosphorus pentasulfide.

Compounds of the invention where X is --NHC(O)OR⁵ are prepared byreacting the 5-aminopyrrolo 3,2-b!pyridine with an appropriatelysubstituted chloroformate in the presence of a suitable amine under theconditions described in the previous paragraph. Likewise, compounds ofthe invention where X is --NR¹ C(O)R⁶ are prepared by reacting the5-aminopyrrolo 3,2-b!pyridine with an appropriate carboxylic acidchloride, bromide or anhydride, optionally in the presence of anacylation catalyst such as dimethylaminopyridine, in the presence of asuitable base, such as those described supra. Alternatively, thereaction may be performed in pyridine, which serves as solvent and base.Under certain circumstances, diacylation of the 5-amino moiety mayoccur. Treatment of the diacylated product with hydrochloric acid atroom temperature provides the monoacylated products of the presentinvention.

Compounds of the invention where X is --NR¹ C(O)R⁶ may also be preparedby reacting the 5-aminopyrrolo 3,2-b!-pyridine with an appropriatecarboxylic acid in the presence of typical peptide coupling reagentssuch as N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide(DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC). A polymer supported form of EDC has been described (TetrahedronLetters, 34(48), 7685 (1993)) and is very useful for the preparation ofthe compounds of the present invention. The product from these reactionsis isolated and purified as described above.

The skilled artisan will appreciate that compounds of the inventionwhere R is hydrogen may be prepared by removal of appropriate R'substituents. Where R' is benzyl, for example, it may be removed byhydrogenolysis. Where R' is (C₁ -C₄ alkoxy)carbonyl, it may be removedby hydrolysis. A particularly useful moiety for these purposes is thetert-butoxycarbonyl moiety which may be removed by treatment withtrifluoroacetic acid at room temperature.

The 5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridines(VI) and 5-amino-3-(piperidin-4-yl)pyrrolo 3,2-b!pyridines (VII)required to prepare the compounds of the present invention are novel andrepresent a further embodiment of the present invention. Those5-amino-3-(piperidin-4-yl)- and5-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridines ofFormula II where R¹ is H (Formula IIa), may be prepared as described inSynthetic Scheme II, where R is as previously defined. ##STR4##

The nitration is performed by adding an equivalent of 90% nitric aciddissolved in an equal volume of concentrated sulfuric acid which hasbeen precooled 0° C. to a solution of 6-amino-2-picoline(6-amino-2-methylpyridine) in five volumes (relative to volume of nitricacid solution) of concentrated sulfuric acid at -6° C. The nitric acidsolution is added at a rate to maintain the temperature of the reactionmixture at about -2° C. The reaction mixture is stirred at about 0° C.for one hour and is then allowed to warm to about 10° C. over an hour.The temperature of the reaction mixture is maintained at about 10° C.for one hour and is then allowed to warm to about 20° C. over an hour.The reaction mixture is maintained at about 20° C. for 2 hours. Thereaction mixture is then poured over ice, made basic (pH about 9) by theaddition of an appropriate hydroxide base, typically potassium, sodium,or ammonium hydroxide, maintaining the temperature at about 20° C. bythe addition of ice as needed. The resulting slurry is filtered, washedwith water, and dried to provide a 2:1 mixture of3-nitro-:5-nitro-6-amino-2-picoline.

The undesired 5-nitro-6-amino-2-picoline isomer may be removed by steamdistillation, sublimation, or by fractional crystallization from asuitable solvent, preferably toluene. The desired3-nitro-6-amino-2-picoline is then reacted with dimethylformamidedimethylacetal or tris(dimethylamino)methane in a suitable solvent,typically dimethylformamide. Once the reaction is complete the reactionmixture is treated with either water or isopropanol to precipitate thedesired intermediate III, which is isolated by filtration.Alternatively, Intermediate III may be prepared by directly subjectingthe mixture of nitration isomers previously described todimethylformamide dimethylacetal or tris(dimethylamino)methane.Treatment of the resulting reaction mixture with water results in theprecipitation of Intermediate III which may be isolated by filtration.

Intermediate III may then be hydrogenated in a lower alkanol, typicallyethanol, in the presence of a palladium catalyst, typically 10%palladium on carbon. Once hydrogenation is complete, the reactionmixture is filtered and the filtrate concentrated under reducedpressure. The desired 5-(dimethylaminomethylimino)pyrrolo 3,2-b!pyridinemay be used as recovered in subsequent reactions or first purified byslurry washing or by silica gel chromatography as necessary or desired.Reacting 5-(dimethylaminomethylimino)pyrrolo 3,2-b!pyridine to anappropriately substituted 4-piperidinone in the presence of a suitablebase, typically potassium or sodium hydroxide or alkoxide, in a suitablesolvent, typically ethanol or methanol, provides the requisiteIntermediate VI. Subjecting Intermediate VI to standard hydrogenationconditions provides Intermediate VII.

Alternatively, Intermediate VII may be prepared by the proceduredescribed in Synthetic Scheme III. ##STR5##

Intermediate III is hydrogenated in methanol containing hydrogenchloride in the presence of a palladium catalyst, typically 10%palladium on carbon. The resulting1-hydroxy-5-(dimethylaminomethaneimino)pyrrolo 3,2-b!pyridinedihydrochloride is isolated by filtration of the reaction mixture andmay be further purified and removed from catalyst by recrystallization.The amidine functionality at the 5-position of the pyrrolo3,2-b!pyridine may be removed to provide the corresponding amine byheating the amidine substrate in ethanol under acidic conditions orunder neutral hydrogenation conditions. The amidine functionality at the5-position may be removed either prior or subsequent to reaction with anappropriate 4-piperidone. Regardless of when the amidine functionalityis removed, the 1-hydroxy substituent is removed by hydrogenation in alower alkanol, typically methanol, in the presence of a palladiumcatalyst, typically 10% palladium on carbon.

Compounds of formula II where R¹ is lower alkyl are prepared byfunctionalizing the amino moiety by an acylation/reduction or reductivealkylation. This chemistry is illustrated in Synthetic Scheme IV, whereM is methoxy, ethoxy, methyl, ethyl, propyl, or isopropyl, LG is chloroor bromo, R¹ ' is C₁ -C₄ alkyl, and A--B and R' are as defined supra.##STR6##

A solution of the 5-amino-pyrrolo 3,2-b!pyridine in a suitable solvent,such as tetrahydrofuran, dioxane, or diethyl ether, at a temperaturefrom about ambient to about 0° C., is reacted with a compound ofstructure M--C(O)--LG in the presence of a suitable base such aspyridine or triethylamine. This acylated product is then dissolved in asuitable solvent, such as tetrahydrofuran or diethyl ether, at atemperature from about ambient to about 0° C., and is treated with asuitable hydride reducing agent such as diborane or lithium aluminumhydride. The reaction is stirred from 1 to 24 hours and is then treatedwith an aqueous solution of sodium sulfate. The resultant suspension isfiltered, and the filtrate concentrated under reduced pressure toprovide the desired product.

Alternatively, a solution of a 5-aminopyrrolo 3,2-b!pyridine in asolvent suitable for the azeotropic removal of water, such as toluene,benzene or cyclohexane, is reacted at reflux with an appropriatealdehyde or ketone, such as formaldehyde, acetaldehyde, propanal,butanal or acetone, in the presence of 0.1-10% of a proton source suchas p-toluenesulfonic acid. When the reaction is complete the volatilesare removed under reduced pressure and the residue redissolved in analkanol such as methanol or ethanol. This solution is then subjected tohydrogenation conditions, or is treated with an appropriate hydridereducing agent, such as sodium borohydride or, preferably, sodiumcyanoborohydride in the presence of an anhydrous acid such as hydrogenchloride. The product is isolated by a normal extractive workup.

Those compounds of the invention where X is --NHSO₂ R² and --NHCOR⁶ maybe prepared in the alternative by the procedure described in SyntheticScheme V where Y is --NHSO₂ R² or --NHCOR⁶, and R, R², and R⁶ are aspreviously described. ##STR7##

The starting 2-methyl-3-nitro-6-aminopyridine (a) is either acylatedwith an appropriate carboxylic acid, anhydride, or acid halide, orreacted with an appropriate sulfonyl halide or anhydride under any ofthe conditions described for Synthetic Scheme I to provide thecorresponding compound (d). This compound is subjected to standard amineoxidizing conditions, for example peracetic acid in acetic acid, toprovide the corresponding N-oxide (e). This N-oxide is then subjected tothe enamine formation, hydrogenation, and condensation sequencedescribed for Synthetic Scheme II to provide the desired compounds ofthe invention. The skilled artisan will appreciate that this alternativeroute is applicable only to those R² and R⁶ substituents which arestable to the various reaction conditions employed. The compounds ofFormula IV are novel and represent a further embodiment of the presentinvention.

Certain compounds of the invention, while useful 5-HT_(1F) agonists intheir own right, are useful intermediates for the preparation of othercompounds of the invention.

Compounds of the invention where X is --NHC(O)OR⁵ or --NR¹ C(O)R⁶, forexample, may be subjected to either acid or base hydrolysis to providethe corresponding 5-amino-3-(piperidin-4-yl)pyrrolo 3,2-b!pyridines.This amine may then be subjected to any of the reaction conditionsdescribed for Synthetic Scheme I to prepare other compounds of theinvention. Furthermore, the skilled artisan will appreciate that many ofthese reactions may be performed in any convenient order. For example,the 5-amino substituent may be modified prior or subsequent to thehydrogenation of the 1,2,3,6-tetrahydropyridin-4-yl moiety if convenientor desired. These variations are made apparent in the followingExamples.

PREPARATION I 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Nitration of 6-amino-2-picoline

110 gm (1.02 mole) molten 6-amino-2-picoline were added dropwise to 500mL concentrated sulfuric acid which had been precooled to -15° C. atrate to maintain the temperature of the sulfuric acid solution under 20°C. The solution was then cooled to about -6° C. and then a solution of49 mL 90% nitric acid (1.16 mole) in 49 mL sulfuric acid precooled toabout 0° C. was added dropwise over about 30 minutes, maintaining thetemperature at about 0° C. The reaction mixture was stirred at about 0°C. for one hour and was then allowed to warm to about 10° C. over anhour. The temperature of the reaction mixture was maintained at about10° C. for one hour and was then allowed to warm to about 20° C. over anhour. The reaction mixture was maintained at about 20° C. for 2 hours.The reaction mixture was poured into 8 L of ice with vigorous stirring.The reaction mixture was then adjusted to pH ˜9 by the addition of 1.5 Lconcentrated ammonium hydroxide, maintaining the temperature of thereaction mixture at about 24° C. by the addition of ice as needed. Theresulting slurry was filtered and the solid washed several times withwater. The solid was dried at 70° C. under vacuum for 3 days to provide135.4 gm (87%) of a 2:1 mixture of 3-nitro-:5-nitro-6-amino-2-picoline.

Separation of nitration isomers by sublimation

20 gm lots of the nitration mixture were sublimed twice under vacuum at125° C. for 6 hours each. The 5-nitro isomer was sublimed as a brightyellow powder and discarded. The 3-nitro isomer which remained in thebottom of the sublimation apparatus was collected. A total of 121 gmwere sublimed to provide 60.9 gm (75.5%) of the crude 3-nitro isomer. 58gm of the crude 3-nitro isomer were slurried in 200 mL hot 95:5ethanol:water. The mixture was cooled to room temperature and dilutedwith 200 mL of water. After two hours the precipitate was collected byfiltration and rinsed several times with water. The solid was driedunder vacuum at room temperature to provide 38 gm (65% based on 58 gmcrude) 3-nitro-6-amino-2-picoline.

MS(m/e): 153 (M⁺); Calculated for C₆ H₇ N₃ O₂ : Theory: C, 47.05; H,4.61; N, 27.44. Found: C, 47.08; H, 4.53; N, 27.53.

Separation of nitration isomers by recrystallization

A mixture of 20 gm of the nitration mixture and 800 mL toluene wereheated at reflux for 15 minutes. The mixture was filtered at 95° C. andthe mother liquors allowed to cool to room temperature. After 4 hoursthe crystalline solid was collected, washed with 100 mL toluene, anddried under reduced pressure at 50° C. for 16 hours to provide 13.7 gm(68%) 3-nitro-6-amino-2-picoline.

Preparation of2-(2-dimethylaminoethen-1-yl)-5-nitro-6-(dimethylaminomethyleneimino)-pyrrolo3,2-b!pyridine (Intermediate III)

A mixture of 60 gm (0.39 mole) 3-nitro-6-amino-2-picoline in 260 mLdimethylformamide was treated with 260 mL (1.83 mole) 94%dimethylformamide dimethylacetal and the solution was heated at refluxfor 48 hours. The reaction was concentrated under reduced pressure andthe residual solid slurried with toluene. The toluene was evaporatedunder reduced pressure. This procedure was repeated 5 times. The finalresidue was slurried with 300 mL methyl tert-butyl ether and thenfiltered. This solid was washed 3 times with 300 mL methyl tert-butylether and the black solid was finally dried under reduced pressure toprovide 90.6 gm (88%) of the desired compound.

MS(m/e): 263.1 (M⁺); Calculated for C₁₂ H₁₇ N₅ O₂ : Theory: C, 54.74; H,6.51; N, 26.60. Found: C, 54.84; H, 6.49; N, 26.79.

Preparation of 5-(dimethylaminomethyleneimino)pyrrolo 3,2-b!pyridine

A mixture of 90 gm (0.34 mole) Intermediate III and 6 gm 10% palladiumon carbon in 650 mL ethanol was hydrogenated at 50 p.s.i. for 45 hours.The reaction mixture was filtered and the was concentrated under reducedpressure. The residual solid was slurried for 30 minutes with 70:30methyl tert-butyl ether:ethyl acetate, filtered and rinsed with 3×300 mL70:30 methyl tert-butyl ether:ethyl acetate. The solid was powdered andthen slurried with 200 mL 70:30 methyl tert-butyl ether:ethyl acetate.The solid was filtered and dried under reduced pressure to provide 54.5gm (85%) of the title compound as a yellow solid.

MS(m/e): 188.2 (M⁺)

Condensation with 1-methyl-4-piperidone

A solution of 19.2 gm (0.10 mole) of5-(dimethylaminomethyleneimino)pyrrolo 3,2-b!pyridine in 208 mL methanolwas treated with 20 gm (0.30 mole) potassium hydroxide followed by 16.3mL (0.13 mMol) 1-methyl-4-piperidone. The reaction mixture was heatedunder reflux for 24 hours and was then concentrated under reducedpressure. The residual solid was treated with 250 mL 9:1 ethylacetate:tetrahydrofuran and 50 mL methanol. The solution was cooled to0° C. and then 200 mL cold water were added. The phases were separatedand the aqueous phase was extracted well with 9:1 ethylacetate:tetrahydrofuran. All organic phases were combined, dried oversodium sulfate and concentrated under reduced pressure. The residualsolid was slurried repeatedly with 475 mL cold water to remove blackimpurities. The remaining solid was dried under reduced pressure toprovide 17 gm (74%) of the title compound as a yellow powder.

MS(m/e): 228.1 (M⁺); Calculated for C₁₃ H₁₆ N₄ : Theory: C, 68.39; H,7.06; N, 24.54. Found: C, 68.13; H, 7.06; N, 24.38.

PREPARATION II 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

A mixture of 21 gm (89.9 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 10% palladium on carbon pre-wet with 30 mL ethanol in180 mL methanol were hydrogenated at 65 p.s.i for 3 days. The catalystwas removed by filtration and the filtrate concentrated under reducedpressure. The residual solid was slurried in 120 mL ethyl acetate,filtered, and washed 3×30 mL ethyl acetate. The remaining solid wasdried under reduced pressure to provide 19 gm (92%) the title compoundas a light brown solid.

MS(m/e): 230 (M⁺); Calculated for C₁₃ H₁₈ N₄ : Theory: C, 67.80; H,7.88; N, 24.32. Found: C, 67.21; H, 7.79; N, 24.24.

PREPARATION III Alternate isolation of Intermediate III

A solution of 38.8 gm (0.25 mole) 3-nitro-6-amino-2-picoline in 172 mLdimethylformamide was treated with 172 mL dimethylformamidedimethylacetal and the mixture was heated at about 97° C. for 42 hours.The reaction mixture was then cooled to room temperature and was dilutedwith 650 mL isopropanol. The reaction mixture was allowed to stand for18 hours at room temperature and was then cooled to 3-5° C. withstirring for an additional 2 hours. The slurry was filtered, the solidwashed 2×75 mL isopropanol, and dried under reduced pressure at 45° C.for 16 hours to provide 58.9 gm (88%) of Intermediate III.

PREPARATION IV Synthesis of Intermediate III from Mixture of NitrationIsomers

A mixture of 133 gm (0.86 mole) of a 2:1 mixture of3-nitro:5-nitro-6-amino-2-picoline in 500 mL dimethylformamide wastreated with 500 mL (3.5 mole) 94% dimethylformamide dimethylacetal andheated at reflux for 40 hours. After cooling to room temperature, thereaction mixture was divided in half and each half was poured into 10 Lof water at 0° C. with vigorous stirring. After 10 minutes, the mixturewas filtered and the solid was slurried/rinsed with 3×1 L of water. Thesolid was dried under vacuum at 65° C. for 2.5 days to provide 183 gm(81%) of the title compound as a red solid.

PREPARATION V Alternate Synthesis of5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Preparation of 1-hydroxy-5-(dimethylaminomethylimino)pyrrolo3,2-b!-pyridine dihydrochloride

A mixture of 23.4 gm (89 mMol) Intermediate III and 0.7 gm 10% palladiumon carbon in 234 mL anhydrous methanol were treated with 140 mL 5.9Nethanolic hydrogen chloride. The resulting mixture was hydrogenated for1.5 hours under an initial hydrogen pressure of 30 p.s.i. The reactionmixture was diluted with 585 mL ethanol and was stirred at roomtemperature for 1 hour at room temperature. The precipitate was filteredand rinsed with 50 mL ethanol. The solid was taken up in 1.1 L methanol,filtered, and then concentrated under reduced pressure. The residualsolid was dried under reduced pressure to provide 20.5 gm (83%) of thedesired compound (containing 5% 5-(dimethylaminomethylimino)pyrrolo3,2-b!pyridine) as a yellow solid.

Preparation of1-hydroxy-5-(dimethylaminomethylimimo)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

A mixture of 13.5 gm (48.7 mMol)1-hydroxy-5-(dimethylaminomethylimino)pyrrolo 3,2-b!pyridine and 17.5 gm(155 mMol) 1-methyl-4-piperidone in 270 mL anhydrous ethanol was stirreduntil homogeneous. At this point 19.4 mL (109 mMol) 5.6N dimethylaminein ethanol were added and the reaction mixture stirred at roomtemperature for 4 hours. The yellow precipitate was filtered, washed2×27 mL ethanol, and dried under reduced pressure at 45° C. to provide13.4 gm (92%) of the desired compound as a yellow solid.

Hydrogenation/hydrogenolysis

A mixture of 0.28 gm (0.94 mMol)1-hydroxy-5-(dimethylaminomethylimimo)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.10 gm 10% palladium on carbon in 20 mL methanol washydrogenated for about 18 hours under an initial hydrogen pressure of 50p.s.i. The reaction mixture was filtered and the filtrate concentratedunder reduced pressure to provide 0.21 gm (96%) of the title compound.

PREPARATION VI5-amino-3-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.75 gm (3.98 mMol) 5-substituted pyrrolo 3,2-b!pyridine(c) and 1.6 gm (7.96 mMol) 1-tert-butoxycarbonyl-4-piperidone, 1.07 gm(86%) of the title compound were prepared as a yellow foam essentiallyby the procedure of Preparation I.

MS(m/e): 314(M⁺); Calculated for C₁₇ H₂₂ N₄ O₂ : Theory: C, 64.95; H,7.05; N, 17.82. Found: C, 64.73; H, 7.09; N, 17.92.

PREPARATION VII 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 1.07 gm (3.4 mMol)5-amino-3-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine, 0.89 gm (83%) of the title compound were preparedessentially by the procedure of Preparation II.

MS(m/e): 316(M⁺)

EXAMPLE 15-(N-acetylamino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Preraration of acetamide (d), R⁶ =CH₃

A mixture of 21.8 gm (142.4 mMol) 2-methyl-3-nitro-6-aminopyridine and28 mL (298.9 mMol) acetic anhydride was heated at 120° C. for 1.5 hours.The reaction mixture was then concentrated under reduced pressure andthe residue slurried in water for 18 hours. The slurry was filtered andthe solid dried under vacuum at 50° C. for 2 hours. The remaining solidwas recrystallized from methanol to provide 23.5 gm (85%) of the desiredcompound as brown needles in two crops.

Preparation of N-oxide (e), R⁶ =CH₃

A solution of 14 mL (66.2 mMol) peracetic acid (4.8M) in aqueous aceticacid was added dropwise to a suspension of 11.8 gm (60.2 mMol) of theacetamide (e) in 30 mL acetic acid. The mixture was stirred at 25° C.for 2 hours and was then gradually warmed to 60° C. and maintained atthat temperature for 18 hours. The reaction mixture was concentratedunder reduced pressure and the residue suspended in 200 mL water. Themixture was cooled and the solid collected by filtration and then driedunder vacuum to provide 11.07 gm (87%) of the desired compound.

Preparation of enamine (f), R⁶ =CH₃

A mixture of 11.1 gm (52.6 mMol) N-oxide (e) and 7.7 mL (57.8 mMol)dimethylformamide dimethylacetal in 25 mL dimethylformamide was heatedat 90° C. for 4 hours. Volatiles were removed under reduced pressure andresidual dimethylformamide removed by azeotropic distillation withtoluene. The residue was subjected to silica gel chromatography, elutingwith a gradient of dichloromethane (1-5% methanol). Fractions containingproduct were combined and concentrated under reduced pressure to provide9.15 gm (65%) of the desired compound as a red solid.

Preparation of 5-(N-acetylamino)pyrrolo 3,2-b!pyridine

A mixture of 9.3 gm (34.9 mMol) of enamine (f) and 4 gm palladium oncarbon in 1 L tetrahydrofuran:ethanol (1:1) was hydrogenated at 60° C.under balloon pressure for 44 hours. At this point the reaction wasfiltered and the filtrated concentrated under reduced pressure. Theresidue was redissolved in 700 mL tetrahydrofuran:ethanol (1:1), 4 gmpalladium on carbon were added, and the mixture was again hydrogenatedat 60° C. under balloon pressure. After 20 hours the reaction mixturewas filtered through celite and the filtrated concentrated under reducedpressure. The residue was subjected to silica gel chromatography,eluting with a gradient of ethyl acetate (5-20% methanol). Fractionscontaining product were combined and concentrated under reduced pressureto provide 4.99 gm (81%) of the desired product as an ivory solid.

Condensation with 1-methyl-4-piperidone

A solution of 0.477 gm (2.7 mMol) of the 5-(N-acetylamino)pyrrolo3,2-b!pyridine, 0.54 mg (9.5 mMol) potassium hydroxide, and 0.43 mL (3.5mMol) 1-methyl-4-piperidone in 15 mL methanol was heated at reflux for18 hours. The reaction mixture was then concentrated under reducedpressure and the residue dissolved in pyridine. To this solution wasadded 0.20 mL (2.2 mMol) acetic anhydride and the resultant mixturestirred for 1 hour. This reaction mixture was concentrated under reducedpressure. The residue was subjected to silica gel chromatography,eluting with a gradient of ethyl acetate (2-40% methanol). Fractionscontaining product were combined and concentrated under reduced pressureto provide 0.43 gm (59%)5-(N-acetylamino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine as an ivory foam. A portion was recrystallized frommethanol/ethyl acetate to provide an analytical sample.

m.p.=191.5-193.0° C. (dec.); MS(m/e): 270(M⁺)

EXAMPLE 2 5-(N-acetylamino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

A mixture of 0.30 gm (1.1 mMol)5-(N-acetylamino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.05 gm 10% palladium on carbon in 15 mL ethanol washydrogenated at room temperature for 18 hours at an initial hydrogenpressure of 50 p.s.i. The reaction mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was subjected to silicagel chromatography, eluting with ethyl acetate containing 20% methanoland 1% ammonium hydroxide. Fractions containing product were combinedand concentrated under reduced pressure to provide the title compound.

m.p.=196-197.5° C. (dec.); MS(m/e): 272(M⁺)

EXAMPLE 3 Alternate preparation of5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

A mixture of 2.5 gm (9.2 mMol)5-(N-acetylamino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine in 40mL 2N hydrochloric acid was heated at reflux for 1 hour. The reactionmixture was cooled to room temperature, concentrated under reducedpressure, basified (pH ˜11) with 2N aqueous sodium hydroxide,concentrated under reduced pressure, and extracted well with 3:1chloroform:isopropanol. The organic extracts were combined, dried overmagnesium sulfate and concentrated under reduced pressure to provide1.98 gm (93%) of the title compound as a brown solid.

MS(m/e): 230(M⁺); Calculated for C₁₃ H₁₈ N₄ : Theory: C, 67.80; H, 7.88;N, 24.33. Found: C, 67.62; H, 7.57; N, 24.54.

EXAMPLE 4 5-(N-cyclopropanecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

A solution of 0.300 gm (1.30 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine in 40 mLpyridine was heated to 50° C. To this solution was added 0.13 mL (1.43mMol) cyclopropanecarbonyl chloride and the reaction mixture was stirredfor 1.5 hours. An additional 0.10 mL of cyclopropanecarbonyl chloridewere added and the reaction mixture was stirred for an additional hour.The reaction mixture was treated with 1.0 mL of water and was thenconcentrated under reduced pressure. The residue was diluted with 3:1chloroform:isopropanol and the solution washed sequentially with water,dilute aqueous sodium hydroxide, and saturated aqueous sodium chloride.The organic phase was then dried over sodium sulfate and concentratedunder reduced pressure. The residue was subjected to radialchromatography (silica gel, 1 mm), eluting with a gradient ofdichloromethane (5-10% methanol) containing 1% ammonium hydroxide.Fractions containing product were combined and concentrated underreduced pressure. The residue was recrystallized from ethanol/water toprovide 0.22 gm (55.9%) of the title compound as a crystalline solid.

MS(m/e): 298(M⁺); Calculated for C₁₇ H₂₂ N₄ O-0.1 H₂ O: Theory: C,68.01; H, 7.45; N, 18.66. Found: C, 68.08; H, 7.52; N, 18.42.

EXAMPLE 5 5-(N-cyclobutanecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.25 gm (1.08 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.136 gm(1.19 mMol) cyclobutanecarbonyl chloride, 0.17 gm (50.8%) of the titlecompound were prepared essentially by the procedure described in Example4.

m.p.=104° C.; MS(m/e): 312(M⁺); Calculated for C₁₈ H₂₄ N₄ O: Theory: C,69.20; H, 7.74; N, 17.93. Found: C, 69.38; H, 7.85; N, 17.85.

EXAMPLE 6 5-(N-cyclopentanecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.080 gm (0.348 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.093 mL(0.766 mMol) cyclopentanecarbonyl chloride, 0.095 gm (84%) of the titlecompound was recovered as an amorphous solid essentially by theprocedure described in Example 4.

m.p.=119.3-120.9° C.; MS(m/e): 326(M⁺)

EXAMPLE 7 5-(N-cyclohexanecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

A solution of 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine in 1.0 mLpyridine was heated to 50° C. To this solution were then added 0.0064 mL(0.048 mMol) cyclohexanecarbonyl chloride and the reaction mixturestirred for 1 hour. The reaction mixture is concentrated under reducedpressure and a solution of the residue in methanol passed over a VARIANBOND ELUT SCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchange columnwhich had been preactivated with 10% acetic acid in methanol. The columnwas washed thoroughly with methanol and then the desired product elutedwith 2M ammonia in methanol. Fractions containing product were combinedand concentrated under reduced pressure to provide 0.013 gm (87.2%) ofthe title compound.

MS(m/e): 341(M+1)

EXAMPLE 8 5-(N- propionyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 2.0 gm (8.7 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.91 mL(10.4 mMol) propionyl chloride, 2.58 gm of the title compound wereprepared as a crude brown foam essentially by the procedure described inExample 4. The residue was subjected to flash silica gel chromatography,eluting with dichloromethane containing 10% methanol and 1% ammoniumhydroxide. Fractions containing product were combined and concentratedunder reduced pressure. This residue was crystallized from ethanol:waterto provide 1.74 gm (70%) of the title compound in two crops.

m.p. =98.9-101° C.; MS(m/e): 286(M⁺); Calculated for C₁₆ H₂₂ N₄ O:Theory: C, 67.11; H, 7.74; N, 19.56. Found: C, 66.97; H, 7.59; N, 19.47.

EXAMPLE 9 5-(N- butyryl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.30 gm (1.3 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.165 mL(1.56 mmol) butyryl chloride, 0.22 gm of the title compound wereprepared as an ivory foam essentially by the procedure described inExample 4. This residue was crystallized from ethanol:water to providematerial for analysis.

MS(m/e): 300(M⁺); Calculated for C₁₇ H₂₄ N₄ O: Theory: C, 67.97; H,8.05; N, 18.65. Found: C, 67.38; H, 7.79; N, 18.32.

EXAMPLE 10 5-(N- pentanoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.01 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.0066 mL(0.048 mMol) pentanoyl chloride, 0.013 gm (91%) of the title compoundwere prepared essentially by the procedure described in Example 7.

MS(m/e): 315(M+1)

EXAMPLE 11 5-(N- hexanoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.01 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.0077 mL(0.048 mMol) hexanoyl chloride, 0.012 gm (84%) of the title compoundwere prepared essentially by the procedure described in Example 7.

MS(m/e): 329(M+1)

EXAMPLE 12 5-(N- octanoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.01 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.01 mL(0.057 mMol) octanoyl chloride, 0.013 gm (83%) of the title compoundwere prepared essentially by the procedure described in Example 7.

MS(m/e): 357(M+1)

EXAMPLE 13 5-(N-2-methylpropanoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.35 gm (0.154 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.20 mL(0.193 mMol) 2-methylpropanoyl chloride, 0.35 gm (75%) of the titlecompound were prepared essentially by the procedure described in Example8.

MS(m/e): 300(M⁺)

EXAMPLE 14 5-(N-3-methylbutanoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.048 mMol3-methylbutanoyl chloride, 0.008 gm (60%) of the title compound wereprepared essentially by the procedure described in Example 7.

MS(m/e): 315(M+1)

EXAMPLE 15 5-(N-2,2-dimethylpropanoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.067 mL(0.048 mMol) 2,2-dimethylpropanoyl chloride, 0.0067 gm (48%) of thetitle compound were prepared essentially by the procedure described inExample 7.

MS(m/e): 315(M⁺)

EXAMPLE 16 5-(N- benzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

To a solution of 0.100 gm (0.43 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine in 3 mL 50%aqueous tetrahydrofuran were added 0.43 mL (0.86 mMol) 2N sodiumhydroxide followed by 0.065 mL (0.56 mMol) benzoyl chloride and theresulting mixture was stirred at room temperature. After about 4 hoursthe reaction mixture was partitioned between dichloromethane and 2Nsodium hydroxide. The phases were separated and the aqueous phaseextracted well with dichloromethane. The organic phases were combined,dried over sodium sulfate and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography, eluting with agradient of dichloromethane (2-10% methanol) containing 1% ammoniumhydroxide. Fractions containing product were combined and concentratedunder reduced pressure to provide 0.095 gm (66%) of the title compound.A portion was recrystallized from ethanol/water to provide an analyticalsample.

m.p.=110.7-113.60° C.; MS(m/e): 334(M⁺); Calculated for C₂₀ H₂₂ N₄ O:Theory: C, 71.83; H, 6.63; N, 16.75. Found: C, 72.05; H, 6.47; N, 16.66.

EXAMPLE 17 5-(N-2-fluorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.085 gm (0.369 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.093 mL(0.776 mMol) 2-fluorobenzoyl chloride, 0.106 gm (82%) of the titlecompound was recovered as a crystalline solid by the procedure describedin Example 16.

m.p.=125-126° C.; MS(m/e): 352(M⁺); Calculated for C₂₀ H₂₁ N₄ OF:Theory: C, 68.16; H, 6.01; N, 15.90. Found: C, 68.44; H, 6.07; N, 15.97.

EXAMPLE 18 5-(N-3-fluorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.085 gm (0.369 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.093 mL(0.776 mMol) 3-fluorobenzoyl chloride, 0.100 gm (77.5%) of the titlecompound was recovered as a crystalline solid by the procedure describedin Example 16.

m.p.=129-130° C.; MS(m/e): 352(M⁺)

EXAMPLE 19 5-(N-4-fluorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

A solution of 1.00 gm (4.3 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine in 85 mLpyridine was heated to 55° C. To this solution were added 0.57 mL (4.8mMol) 4-fluorobenzoyl chloride and the resulting mixture was stirred for30 minutes at which time an additional 0.10 mL 4-fluorobenzoyl chloridewere added. After stirring for an additional 10 minutes the reactionmixture was concentrated under reduced pressure. The residue was treatedwith 50 mL cold 1N sodium hydroxide followed by 100 mL dichloromethane.The phases were separated and the aqueous phase was extracted 2×50 mLdichloromethane followed by 3×50 mL 3:1 chloroform:isopropanol. Theorganic phases were combined, washed with saturated aqueous sodiumchloride, dried over magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to radial chromatography (4 mmsilica gel plate) eluting with dichloromethane containing 10-20%methanol and 1% ammonium hydroxide. Fractions containing product werecombined and concentrated under reduced pressure. The residue wascrystallized from aqueous ethanol to provide 1.32 gm (87%) of the titlecompound as ivory crystals.

MS(m/e): 352(M⁺); Calculated for C₂₀ H₂₁ N₄ OF: Theory: C, 68.16; H,6.01; N, 15.90. Found: C, 68.01; H, 5.96; N, 15.88.

EXAMPLE 20 5-(N-3-chlorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.085 gm (0.369 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.099 mL(0.776 mMol) 3-chlorobenzoyl chloride, 0.109 gm (80.1%) of the titlecompound was recovered as a crystalline solid by the procedure describedin Example 16.

m.p.=110-111° C.; MS(m/e): 368(M⁺)

EXAMPLE 21 5-(N- 4-bromobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.090 gm (0.39 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.128 gm(0.59 mMol) 4-bromobenzoyl chloride, 0.053 gm (23%) of the titlecompound was recovered as a crystalline solid by the procedure describedin Example 4.

Calculated for C₂₀ H₂₁ N₄ OBr: Theory: C, 58.12; H, 5.12; N, 13.56.Found: C, 58.41; H, 5.04; N, 13.74.

EXAMPLE 22 5-(N- 4-iodobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.090 gm (0.39 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.157 gm(0.59 mMol) 4-iodobenzoyl chloride, 0.035 gm (19%) of the title compoundwas recovered as a crystalline solid by the procedure described inExample 4.

Calculated for C₂₀ H₂₁ N₄ OI: Theory: C, 52.19; H, 4.60; N, 12.17.Found: C, 52.39; H, 4.79; N, 12.35.

EXAMPLE 23 5-(N- 4-cyanobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.100 gm (0.43 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.093 gm(0.56 mMol) 4-cyanobenzoyl chloride, 0.068 gm (44%) of the titlecompound was recovered as a crystalline solid by the procedure describedin Example 4.

m.p.=129.2-133.6° C.; MS(m/e): 359(M⁺); Calculated for C₂₁ H₂₁ N₅ O:Theory: C, 70.18; H, 5.89; N, 19.48. Found: C, 70.43; H, 5.85; N, 19.61.

EXAMPLE 24 5-(N- 4-nitrobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.100 gm (0.43 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.103 gm(0.56 mMol) 4-nitrobenzoyl chloride, 0.058 gm (36%) of the titlecompound was recovered as a crystalline solid by the procedure describedin Example 4.

m.p.=235.8-238.0° C. (dec.); MS(m/e): 379(M⁺); Calculated for C₂₀ H₂₅ N₅O₃ : Theory: C, 63.31; H, 5.58; N, 18.46. Found: C, 63.12; H, 5.83; N,18.61.

EXAMPLE 25 5-(N-2,4-dichlorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.085 gm (0.369 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.108 mL(0.776 mmol) 2,4-dichlorobenzoyl chloride, 0.108 gm (72.7%) of the titlecompound was recovered as an amorphous solid by the procedure describedin Example 16.

m.p.=151-152° C.; MS(m/e): 402(M⁺); Calculated for C₂₀ H₂₀ N₄ OCl₂ :Theory: C, 59.56; H, 5.00; N, 13.89. Found: C, 59.69; H, 5.10; N, 14.15.

EXAMPLE 26 5-(N-3-pyridinecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.078 gm (0.339 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.127 gm(0.712 mMol) 3-pyridinecarbonyl chloride hydrochloride, 0.106 gm (82%)of the title compound was recovered as a crystalline solid by theprocedure described in Example 16.

m.p.=136-137° C.; MS(m/e): 335(M⁺)

EXAMPLE 27 5-(N-4-pyridinecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.065 gm (0.282 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.106 gm(0.593 mMol) 4-pyridinecarbonyl chloride hydrochloride, 0.053 gm (56%)of the title compound was recovered as an amorphous solid by theprocedure described in Example 16.

m.p.=126.5-128.40° C. MS(m/e): 335(M⁺)

EXAMPLE 28 5-(N- 2-furoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.200 gm (0.87 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.171 mL(1.74 mMol) 2-furoyl chloride, 0.090 gm (32%) of the title compound wasrecovered as a crystalline solid from methanol/ethyl acetate by theprocedure described in Example 16.

m.p.=251.0-253.3° C. (dec.); MS(m/e): 324(M⁺); Calculated for C₁₈ H₂₀ N₄O₂ : Theory: C, 66.65; H, 6.21; N, 17.27. Found: C, 66.88; H, 6.34; N,17.45.

EXAMPLE 29 5-(N-2-thiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.100 gm (0.43 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.056 mL(0.52 mMol) 2-thiophenecarbonyl chloride, 0.052 gm (34%) of the titlecompound was recovered as a crystalline solid by the procedure describedin Example 4.

MS(m/e): 340(M⁺); Calculated for C₁₈ H₂₀ N₄ OS: Theory: C, 63.50; H,5.92; N, 16.46. Found: C, 63.21; H, 6.10; N, 16.39.

EXAMPLE 30 5-(N-2-chlorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.0067 mL(0.053 mMol) 2-chlorobenzoyl chloride, 0.015 gm (91%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 369(M⁺)

EXAMPLE 31 5-(N- 2-bromobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.065 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.0099 mL(0.072 mMol) 2-bromobenzoyl chloride, 0.026 gm (96%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 412(M⁺)

EXAMPLE 32 5-(N- 3-bromobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.065 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.0095 mL(0.072 mMol) 3-bromobenzoyl chloride, 0.024 gm (90%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 412(M⁺)

EXAMPLE 33 5-(N- 3-cyanobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.065 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.012 gm(0.072 mMol) 3-cyanobenzoyl chloride, 0.021 gm (92%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 359(M⁺)

EXAMPLE 34 5-(N-2-methylbenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.015 gm (0.065 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.0094 mL(0.072 mMol) 2-methylbenzoyl chloride, 0.023 gm (100%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 348(M⁺)

EXAMPLE 35 5-(N-3-methylbenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.015 gm (0.065 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.0095 mL(0.072 mMol) 3-methylbenzoyl chloride, 0.022 gm (99%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 348(M⁺)

EXAMPLE 36 5-(N-4-methylbenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.007 mL(0.058 mMol) 4-methylbenzoyl chloride, 0.010 gm (66%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 349(M+1)

EXAMPLE 37 5-(N-4-tert-butylbenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.011 mL(0.057 mMol) 4-tert-butylbenzoyl chloride, 0.013 gm (76%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 391(M+1)

EXAMPLE 38 5-(N-2-trifluoromethylbenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.008 mL(0.053 mMol) 2-trifluoromethylbenzoyl chloride, 0.017 gm (96%) of thetitle compound were prepared essentially by the procedure described inExample 7.

MS(m/e): 403(M+1)

EXAMPLE 39 5-(N-4-trifluoromethylbenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.008 mL(0.058 mMol) 4-trifluoromethylbenzoyl chloride, 0.013 gm (73%) of thetitle compound were prepared essentially by the procedure described inExample 7.

MS(m/e): 403(M+1)

EXAMPLE 40 5-(N-2-methoxybenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.008 mL(0.058 mMol) 2-methoxybenzoyl chloride, 0.006 gm (39%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 365(M+1)

EXAMPLE 41 5-(N-3-methoxybenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.004 mL(0.058 mMol) 3-methoxybenzoyl chloride, 0.016 gm (98%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 365(M+1)

EXAMPLE 42 5-(N-4-methoxybenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.058 mMol4-methoxybenzoyl chloride, the title compound was prepared essentiallyby the procedure described in Example 7.

MS(m/e): 364(M⁺)

EXAMPLE 43 5-(N-4-trifluoromethoxybenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.012 mL(0.053 mMol) 4-trifluoromethoxybenzoyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 419(M+1)

EXAMPLE 44 5-(N- 2-nitrobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.007 mL(0.048 mMol) 2-nitrobenzoyl chloride, 0.015 gm (92%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 380(M+1)

EXAMPLE 45 5-(N- 3-nitrobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.048 mMol3-nitrobenzoyl chloride, the title compound was prepared essentially bythe procedure described in Example 7.

MS(m/e): 380(M+1)

EXAMPLE 46 5-(N-3,4-difluorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.007 mL(0.055 mMol) 3,4-difluorobenzoyl chloride, 0.014 gm (80%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 371(M+1)

EXAMPLE 47 5-(N-2,4-difluorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.006 mL(0.053 mMol) 2,4-difluorobenzoyl chloride, 0.012 gm (77%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e): 371(M+1)

EXAMPLE 48 5-(N-2,6-difluorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.007 mL(0.053 mMol) 2,6-difluorobenzoyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 371(M+1)

EXAMPLE 49 5-(N-2-fluoro-4-trifluoromethylbenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.012 mL(0.053 mMol) 2-fluoro-4-trifluoromethylbenzoyl chloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 421(M+1)

EXAMPLE 50 5-(N-2,4,5-trifluorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.007 mL(0.055 mMol) 2,4,5-trifluorobenzoyl chloride, 0.015 gm (86%) of thetitle compound were prepared essentially by the procedure described inExample 7.

MS(m/e): 389(M+1)

EXAMPLE 51 5-(N-2,3,4,5,6-pentafluorobenzoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.008 mL(0.053 mMol) 2,3,4,5,6-pentafluorobenzoyl chloride, 0.016 gm (84%) ofthe title compound were prepared essentially by the procedure describedin Example 7.

MS(m/e): 425(M+1)

EXAMPLE 52 5-(N- 3-furoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 1.0 gm (4.3 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.68 gm(5.2 mMol) 3-furoyl chloride, 0.85 gm (61%) of the title compound wereprepared as an ivory crystalline solid essentially by the proceduredescribed in Example 4.

m.p.=105.3-108.4° C.; MS(m/e); 324(M⁺)

EXAMPLE 53 5-(N-5-nitro-2-furoyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.10 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.0093 mL(0.053 mMol) 5-nitro-2-furoyl chloride, 0.010 gm (64%) of the titlecompound were prepared essentially by the procedure described in Example7.

MS(m/e). 370(M+1)

EXAMPLE 54 5-(N-3-thiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 1.5 gm (6.5 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 1.2 gm (7.8mMol) 3-thiophenecarbonyl chloride, 1.42 gm (64%) of the title compoundwere prepared essentially by the procedure described in Example 4.

m.p.=123.2-126.8° C.; MS(m/e): 340(M⁺); Calculated for C₁₈ H₂₀ N₄ OS:Theory: C, 63.50; H, 5.92; N, 16.46. Found: C, 63.61; H, 5.94; N, 16.33.

EXAMPLE 55 5-(N-5-fluoro-2-thiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.414 gm (1.8 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 2.73 mMol5-fluoro-2-thiophenecarbonyl chloride, 0.11 gm (17%) of the titlecompound were prepared essentially by the procedure described in Example4.

m.p.=244-245° C.; MS(m/e): 358(M⁺); Calculated for C₁₈ H₁₉ FN₄ OS:Theory: C, 60.32; H, 5.34; N, 15.63. Found: C, 60.59; H, 5.34; N, 15.72.

EXAMPLE 56 5-(N-3-chloro-2-thiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.30 gm (1.3 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.29 gm(1.56 mMol) 3-chloro-2-thiophenecarbonyl chloride, 0.28 gm (57%) of thetitle compound were prepared as an orange foam essentially by theprocedure described in Example 4.

m.p.=255° C. (dec.); MS(m/e): 374(M⁺); Calculated for C₁₈ H₁₉ ClN₄ OS:Theory: C, 57.67; H, 5.11; N, 14.94. Found: C, 57.58; H, 5.20; N, 15.32.

EXAMPLE 57 5-(N-5-chloro-2-thiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.30 gm (1.3 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.29 gm(1.56 mMol) 5-chloro-2-thiophenecarbonyl chloride, 0.36 gm (75%) of thetitle compound were prepared essentially by the procedure described inExample 4.

m.p.=117.7-120.4° C.; MS(m/e): 374(M⁺); Calculated for C₁₈ H₁₉ ClN₄ OS:Theory: C, 57.67; H, 5.11; N, 14.94. Found: C, 57.68; H, 5.21; N, 14.67.

EXAMPLE 58 5-(N-3-bromo-2-thiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.37 gm (1.6 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.45 gm(2.0 mMol) 3-bromo-2-thiophenecarbonyl chloride, 0.33 gm (49%) of thetitle compound were prepared essentially by the procedure described inExample 8.

m.p.=245-247° C.; MS(m/e): 420(M+1); Calculated for C₁₈ H₁₉ BrN₄ OS:Theory: C, 51.56; H, 4.57; N, 13.36. Found: C, 51.54; H, 4.57; N, 13.31.

EXAMPLE 59 5-(N-3-methyl-2-thiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.40 gm (1.74 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.34 gm(2.08 mMol) 3-methyl-2-thiophenecarbonyl chloride, 0.51 gm (83%) of thetitle compound were prepared as a light brown foam essentially by theprocedure described in Example 4. A sample was crystallized fromethanol/water for analysis.

m.p.=208.5-210.7° C.; MS(m/e): 354(M⁺); Calculated for C₁₉ H₂₂ N₄ OS:Theory: C, 64.38; H, 6.26; N, 15.81. Found: C, 64.14; H, 6.10; N, 15.89.

EXAMPLE 60 5-(N-5-methyl-2-thiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.40 gm (1.74 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.34 gm(2.08 mMol) 5-methyl-2-thiophenecarbonyl chloride, 0.53 gm (86%) of thetitle compound were prepared essentially by the procedure described inExample 4.

m.p.=123.2-127.4° C.; MS(m/e): 355(M+1); Calculated for C₁₉ H₂₂ N₄ OS:Theory: C, 64.38; H, 6.26; N, 15.81. Found: C, 64.17; H, 6.17; N, 15.61.

EXAMPLE 61 5-(N-2,5-dimethyl-4-thiazolecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.34 gm (1.6 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.44 gm(2.50 mMol) 2,5-dimethyl-4-thiazolecarbonyl chloride, the title compoundwas prepared essentially by the procedure described in Example 4.

m.p.=125-126° C.; MS(m/e): 369(M⁺); Calculated for C₁₉ H₂₃ N₅ OS:Theory: C, 61.76; H, 6.27; N, 18.95. Found: C, 61.80; H, 6.37; N, 18.99.

EXAMPLE 62 5-(N-2-pyridinecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.30 gm (1.30 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.34 gm(1.56 mMol) 2-pyridinecarbonyl chloride, 0.098 gm (26%) of the titlecompound were prepared as a crystalline solid essentially by theprocedure described in Example 4.

m.p.=221.0-223.3° C.; MS(m/e): 335(M⁺)

EXAMPLE 63 5-(N-2-chloro-3-pyridinecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.054 mMol2-chloro-3-pyridinecarbonyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 370(M⁺)

EXAMPLE 64 5-(N-6-chloro-3-pyridinecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.054 mMol6-chloro-3-pyridinecarbonyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 370(M⁺)

EXAMPLE 65 5-(N-2-benzothiophenecarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.41 gm (1.8 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.46 gm(2.33 mMol) 2-benzothiophenecarbonyl chloride, 0.32 gm (46%) of thetitle compound were prepared essentially by the procedure described inExample 4.

m.p.=202-204° C.; MS(m/e): 390(M⁺); Calculated for C₂₂ H₂₂ N₄ OS:Theory: C, 67.67; H, 5.68; N, 14.35. Found: C, 67.79; H, 5.61; N, 14.26.

EXAMPLE 66 5-(N-3-methoxycarbonylpropionyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.007 mL(0.057 mMol) 3-methoxycarbonylpropionyl chloride, 0.01 gm (67%) of thetitle compound were prepared essentially by the procedure described inExample 7.

MS(m/e): 345(M+1)

EXAMPLE 67 5-(N- cyclopropanecarbonyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.005 mL (0.062 mMol) cyclopropanecarbonyl chloride, 5-(N-cyclopropanecarbonyl!amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo3,2-b!pyridine was prepared essentially by the procedure described inExample 7. This compound was dissolved in 10% trifluoroacetic acid indichloromethane and the reaction mixture was stirred at room temperaturefor 1 hour. The volatiles were removed under reduced pressure and theresidue dissolved in methanol. This methanol solution was passed over aVARIAN BOND ELUT SCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchangecolumn which had been preactivated with 10% acetic acid in methanol. Thecolumn was washed thoroughly with methanol and then the desired producteluted with 2M ammonia in methanol. Fractions containing product werecombined and concentrated under reduced pressure to provide the titlecompound.

MS(m/e): 284(M⁺)

The compounds of Examples 68-76 were prepared essentially by theprocedure described in detail in Example 67.

EXAMPLE 68 5-(N- acetyl!amino)-3-(piperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.004 mL (0.062 mMol) acetyl chloride, the title compound wasprepared.

MS(m/e): 258(M⁺)

EXAMPLE 69 5-(N- propionyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.005 mL (0.062 mMol) propionyl chloride, the title compound wasprepared.

MS(m/e): 273(M⁺)

EXAMPLE 70 5-(N- benzoyl!amino)-3-(piperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.007 mL (0.062 mMol) benzoyl chloride, the title compound wasprepared.

MS(m/e) 320(M⁺)

EXAMPLE 71 5-(N- 4-fluorobenzoyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.007 mL (0.062 mMol) 4-fluorobenzoyl chloride, the title compoundwas prepared.

MS(m/e): 338(M⁺)

EXAMPLE 72 5-(N- 2-thiophenecarbonyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.006 mL (0.062 mMol) 2-thiophenecarbonyl chloride, the titlecompound was prepared.

MS(m/e): 326 (M⁺)

EXAMPLE 73 5-(N- 2-furoyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.006 mL (0.062 mMol) 2-furoyl chloride, the title compound wasprepared.

MS(m/e): 310(M⁺)

EXAMPLE 74 5-(N- 3-furoyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.008 mL (0.062 mMol) 3-furoyl chloride, the title compound wasprepared.

MS(m/e): 310(M⁺)

EXAMPLE 75 5-(N- 3-thiophenecarbonyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.009 mL (0.062 mMol) 3-thiophenecarbonyl chloride, the titlecompound was prepared.

MS(m/e): 326(M⁺)

EXAMPLE 76 5-(N- 4-pyridinecarbonyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 0.011 gm (0.062 mMol) 4-pyridinecarbonyl chloride, the titlecompound was prepared.

MS(m/e): 322(M⁺)

EXAMPLE 77 5-(N-cyclopropanecarbonyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.008 mL(0.080 mMol) cyclopropanecarbonyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 312(M⁺)

EXAMPLE 78 5-(N- acetyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.006 mL(0.080 mMol) acetyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 287(M+1)

EXAMPLE 79 5-(N- propionyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.007 mL(0.080 mMol) propionyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 301(M+1)

EXAMPLE 80 5-(N- benzoyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.009 mL(0.080 mMol) benzoyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 349(M⁺)

EXAMPLE 81 5-(N- 4-fluorobenzoyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.009 mL(0.080 mMol) 4-fluorobenzoyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 367(M⁺)

EXAMPLE 82 5-(N- 2-furoyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.008 mL(0.080 mMol) furoyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 338(M⁺)

EXAMPLE 83 5-(N- 3-furoyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.010 mL(0.080 mMol) 3-furoyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 338(M⁺)

EXAMPLE 84 5-(N-2-thiophenecarbonyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.009 mL(0.080 mMol) 2-thiophenecarbonyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 355(M⁺)

EXAMPLE 85 5-(N-3-thiophenecarbonyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.012 mL(0.080 mMol) 3-thiophenecarbonyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 355(M⁺)

EXAMPLE 86 5-(N-4-pyridinecarbonyl!amino)-3-(1-ethylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.061 mMol)5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.014 gm(0.080 mMol) 4-pyridinecarbonyl chloride hydrochloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 350(M⁺)

EXAMPLE 87 5-(N- propionyl!amino)-3-(1-propylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.10 gm (0.39 mMol)5-amino-3-(1-propylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.040 mL(0.046 mMol) propionyl chloride, 0.099 gm (81%) of the title compoundwere prepared as an ivory foam essentially by the procedure described inExample 4. An analytical sample was crystallized from aqueous ethanol.

m.p.=89-91.1° C.; MS(m/e): 314(M⁺); Calculated for C₁₈ H₂₆ N₄ O: Theory:C, 68.76; H, 8.33; N, 17.82. Found: C, 68.73; H, 8.49; N, 17.85.

EXAMPLE 87 5-(N-4-fluorobenzoyl!amino)-3-(1-propylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.10 gm (0.39 mMol)5-amino-3-(1-propylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.055 mL(0.046 mMol) 4-fluorobenzoyl chloride, 0.099 gm (67%) of the titlecompound were prepared as an ivory foam essentially by the proceduredescribed in Example 4. An analytical sample was crystallized fromaqueous ethanol.

m.p.=216.7° C. (dec.); MS(m/e): 380(M⁺);

EXAMPLE 89 5-(N- propionyl!amino)-3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.10 gm (0.39 mMol)5-amino-3-(1-isopropylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.040 mL(0.046 mMol) propionyl chloride, 0.092 gm (75%) of the title compoundwere prepared as an ivory foam essentially by the procedure described inExample 4. An analytical sample was crystallized from aqueous ethanol.

m.p.=94.1-95.8° C.; MS(m/e): 314(M⁺); Calculated for C₁₈ H₂₆ N₄ O:Theory: C, 68.76; H, 8.33; N, 17.82. Found: C, 68.57; H, 8.37; N, 17.67.

EXAMPLE 90 5-(N-4-fluorobenzoyl!amino)-3-(1-isopropylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.10 gm (0.39 mMol)5-amino-3-(1-isopropylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.055 mL(0.046 mMol) 4-fluorobenzoyl chloride, 0.085 gm (58%) of the titlecompound were prepared as an ivory foam essentially by the proceduredescribed in Example 4. An analytical sample was crystallized fromaqueous ethanol.

m.p.=101.0-103.5° C.; MS(m/e): 380(M⁺); Calculated for C₂₂ H₂₅ N₄ OF:Theory: C, 69.45; H, 6.62; N, 14.73. Found: C, 69.54; H, 6.66; N, 14.65.

EXAMPLE 91 5-(N- propionyl!amino)-3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.15 gm (0.55 mMol)5-amino-3-(1-butylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.058 mL(0.067 mMol) propionyl chloride, 0.062 gm (35%) of the title compoundwere prepared as an ivory foam essentially by the procedure described inExample 4. An analytical sample was crystallized from aqueous ethanol.

MS(m/e): 328(M⁺); Calculated for C₁₉ H₂₈ N₄ O: Theory: C, 69.48; H,8.59; N, 17.06. Found: C, 69.77; H, 8.69; N, 17.12.

EXAMPLE 92 5-(N- 4-fluorobenzoyl!amino)-3-(1-butylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.15 gm (0.55 mMol)5-amino-3-(1-butylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.079 mL(0.067 mMol) 4-fluorobenzoyl chloride, 0.094 gm (43%) of the titlecompound were prepared as an ivory foam essentially by the proceduredescribed in Example 4. An analytical sample was crystallized fromaqueous ethanol.

MS(m/e): 394(M⁺); Calculated for C₂₃ H₂₇ N₄ OF: Theory: C, 70.03; H,6.90; N, 14.20. Found: C, 70.19; H, 6.75; N, 14.55.

EXAMPLE 93 5-(N-cyclopropanecarbonyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.006 mL (0.061 mMol) cyclopropanecarbonyl chloride, the title compoundwas prepared essentially by the procedure described in Example 7.

MS(m/e): 389(M+1)

EXAMPLE 94 5-(N-acetyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.004 mL (0.061 mMol) acetyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 363(M+1)

EXAMPLE 95 5-(N-propionyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.005 mL (0.061 mMol) propionyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 377(M+1)

EXAMPLE 96 5-(N-benzoyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.007 mL (0.061 mMol) benzoyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 424(M⁺)

EXAMPLE 97 5-(N-4-fluorobenzoyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.007 mL (0.061 mMol) 4-fluorobenzoyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 442 (M⁺)

EXAMPLE 98 5-(N-2-furoyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.006 mL (0.061 mMol) furoyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 414(M⁺)

EXAMPLE 99 5-(N- 3-furoyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.008 mL (0.061 mMol) 3-furoyl chloride, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 414(M⁺)

EXAMPLE 100 5-(N-2-thiophenecarbonyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.006 mL (0.061 mMol) 2-thiophenecarbonyl chloride, the title compoundwas prepared essentially by the procedure described in Example 7.

MS(m/e): 431(M+1)

EXAMPLE 101 5-(N-3-thiophenecarbonyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.009 mL (0.061 mMol) 3-thiophenecarbonyl chloride, the title compoundwas prepared essentially by the procedure described in Example 7.

MS(m/e): 431(M+1)

EXAMPLE 102 5-(N-4-pyridinecarbonyl!amino)-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo 3,2-b!pyridine and0.011 mL (0.061 mMol) 4-pyridinecarbonyl chloride hydrochloride, thetitle compound was prepared essentially by the procedure described inExample 7.

MS(m/e): 426(M+1)

EXAMPLE 103 5-(N-4-fluorobenzoyl!amino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.200 gm (0.88 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.114 mL (0.96 mMol) 4-fluorobenzoyl chloride, 0.260gm (84%) of the title compound were prepared as an ivory solidessentially by the procedure described in Example 4. An analyticalsample was crystallized from aqueous ethanol.

m.p.=215° C. (dec.); MS(m/e): 350(M⁺); Calculated for C₂₀ H₁₉ N₄ OF:Theory: C, 68.56; H, 5.47; N, 15.99. Found: C, 68.57; H, 5.66; N, 16.01.

EXAMPLE 104 5-(N-4-pyridinecarbonyl!amino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.200 gm (0.88 mMol)5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.188 gm (1.06 mMol) 4-pyridinecarbonyl chloridehydrochloride, 0.180 gm (61%) of the title compound were prepared as anivory solid essentially by the procedure described in Example 8. Ananalytical sample was crystallized from aqueous ethanol.

m.p.=202.8° C. (dec.); MS(m/e): 333(M⁺); Calculated for C₁₉ H₁₉ N₅ O:Theory: C, 68.45; H, 5.74; N, 21.01. Found: C, 68.28; H, 5.68; N, 21.21.

EXAMPLE 105 5-(N-cyclopropanecarbonyl!amino)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.062 mMol)5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridineand 0.006 mL (0.068 mMol) cyclopropanecarbonyl chloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 311(M+1)

EXAMPLE 106 5-(N-acetyl!amino)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.062 mMol)5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridineand 0.005 mL (0.068 mMol) acetyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 285(M+1)

EXAMPLE 107 5-(N-benzoyl!amino)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.062 mMol)5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridineand 0.008 mL (0.068 mMol) benzoyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 346(M+1)

EXAMPLE 108 5-(N-4-fluorobenzoyl!amino)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.062 mMol)5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridineand 0.008 mL (0.068 mmol) 4-fluorobenzoyl chloride, the title compoundwas prepared essentially by the procedure described in Example 7.

MS(m/e): 365(M+1)

EXAMPLE 109 5-(N-2-furoyl!amino)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.062 mMol)5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridineand 0.007 mL (0.068 mMol) 2-furoyl chloride, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 337(M+1)

EXAMPLE 110 5-(N-2-thiophenecarbonyl!amino)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.062 mMol)5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridineand 0.007 mL (0.068 mMol) 2-thiophenecarbonyl chloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 353(M+1)

EXAMPLE 111 5-(N-ethoxycarbonyl!amino)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.062 mMol)5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo 3,2-b!pyridineand 0.006 mL (0.068 mMol) ethyl chloroformate, the title compound wasprepared essentially by the procedure described in Example 7.

MS(m/e): 315(M+1)

EXAMPLE 112 5-(N-cyclopropylcarbonyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.006 mL (0.061 mMol) cyclopropylcarbonyl chloride,the title compound was prepared essentially by the procedure describedin Example 7.

MS(m/e): 387(M+1)

EXAMPLE 113 5-(N-acetyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.004 mL (0.061 mMol) acetyl chloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 361(M+1)

EXAMPLE 114 5-(N-propionyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.005 mL (0.061 mMol) propionyl chloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 375(M+1)

EXAMPLE 115 5-(N-benzoyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.007 mL (0.061 mMol) benzoyl chloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 423(M+1)

EXAMPLE 116 5-(N-4-fluorobenzoyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.007 mL (0.061 mMol) 4-fluorobenzoyl chloride, thetitle compound was prepared essentially by the procedure described inExample 7.

MS(m/e): 441(M+1)

EXAMPLE 117 5-(N-2-furoyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.006 mL (0.061 mMol) 2-furoyl chloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 413(M+1)

EXAMPLE 118 5-(N-3-furoyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.008 mL (0.061 mMol) 3-furoyl chloride, the titlecompound was prepared essentially by the procedure described in Example7.

MS(m/e): 413(M+1)

EXAMPLE 119 5-(N-2-thiophenecarbonyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.007 mL (0.061 mMol) 2-thiophenecarbonyl chloride,the title compound was prepared essentially by the procedure describedin Example 7.

MS(m/e): 429(M⁺)

EXAMPLE 120 5-(N-3-thiophenecarbonyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mMol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.009 mL (0.061 mMol) 3-thiophenecarbonyl chloride,the title compound was prepared essentially by the procedure describedin Example 7.

MS(m/e): 429(M⁺)

EXAMPLE 121 5-(N-4-pyridinecarbonyl!amino)-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.015 gm (0.047 mmol)5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo3,2-b!pyridine and 0.011 mL (0.061 mMol) 4-pyridinecarbonyl chloride,the title compound was prepared essentially by the procedure describedin Example 7.

MS(m/e): 424(M+1)

EXAMPLE 122 N- methyl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!urea

A solution of 0.15 gm (0.65 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.046 mL(0.78 mMol) methyl isocyanate in 6 mL 5:1tetrahydrofuran:dimethylformamide was stirred at room temperature for 5hours. At this point an additional 0.020 mL methyl isocyanate were addedand stirring continued for another 3.5 hours. The reaction mixture wasthen concentrated under reduced pressure. The residue was partitionedbetween 3:1 chloroform:isopropanol and 1N sodium hydroxide. The phaseswere separated and the aqueous phase extracted well with 3:1chloroform:isopropanol. The organic phases were combined, washed withsaturated aqueous sodium chloride, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to radialchromatography (2 mm silica gel plate), eluting with dichloromethanecontaining from 20-40% methanol and 1% ammonium hydroxide. Fractionsshown to contain product were combined and concentrated under reducedpressure. The residue was crystallized from aqueous ethanol to provide0.043 gm (34%) of the title compound.

m.p.=228.8-230.4° C.; MS(m/e): 288(M+1); Calculated for C₁₅ H₂₁ N₅ O:Theory: C, 62.70; H, 7.37; N, 24.37. Found: C, 62.49; H, 7.29; N, 24.40.

EXAMPLE 123 N- ethyl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!urea

Beginning with 0.15 gm (0.65 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.067 mL(0.85 mMol) ethyl isocyanate, 0.137 gm (70%) of the title compound wererecovered essentially by the procedure of Example 122. An analyticalsample was crystallized from aqueous ethanol.

m.p.=212.6° C. (dec.); MS(m/e): 301(M⁺); Calculated for C₁₆ H₂₃ N₅ O:Theory: C, 63.76; H, 7.69; N, 23.24. Found: C, 63.29; H, 7.98; N, 22.89.

EXAMPLE 124 N- propyl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!urea

Beginning with 0.15 gm (0.65 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.073 mL(0.78 mMol) propyl isocyanate, 0.107 gm (52%) of the title compound wererecovered essentially by the procedure of Example 122. An analyticalsample was crystallized from aqueous ethanol.

m.p.=181° C. (dec.); MS(m/e): 315(M⁺); Calculated for C₁₇ H₂₅ N₅ O:Theory: C, 64.74; H, 7.99; N, 22.2. Found: C, 64.51; H, 7.77; N, 22.46.

EXAMPLE 125 N- butyl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!urea

Beginning with 0.15 gm (0.65 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.088 mL(0.78 mMol) butyl isocyanate, 0.168 gm (78%) of the title compound wererecovered essentially by the procedure of Example 122. An analyticalsample was crystallized from aqueous ethanol.

MS(m/e): 329(M⁺)

EXAMPLE 126 N- isopropyl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!urea

Beginning with 0.15 gm (0.65 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.077 mL(0.78 mMol) isopropyl isocyanate, 0.146 gm (71%) of the title compoundwere recovered essentially by the procedure of Example 122. Ananalytical sample was crystallized from aqueous ethanol.

m.p.=217-219° C. (dec.); MS(m/e): 315(M⁺); Calculated for C₁₇ H₂₅ N₅ O:Theory: C, 64.74; H, 7.99; N, 22.20. Found: C, 64.84; H, 8.06; N, 22.44.

EXAMPLE 127 N- prop-1-en-3-yl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!urea

Beginning with 0.15 gm (0.65 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.070 mL(0.78 mMol) prop-1-en-3-yl isocyanate, 0.149 gm (73%) of the titlecompound were recovered essentially by the procedure of Example 122. Ananalytical sample was crystallized from aqueous ethanol.

m.p.=203° C. (dec.); MS(m/e): 313(M⁺); Calculated for C₁₇ H₂₃ N₅ O:Theory: C, 65.15; H, 7.40; N, 22.35. Found: C, 65.15; H, 7.65; N, 22.22.

EXAMPLE 128 N- phenyl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!urea

Beginning with 0.15 gm (0.65 mmol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.092 mL(0.85 mMol) phenyl isocyanate, 0.137 gm (60%) of the title compound wererecovered essentially by the procedure of Example 122. An analyticalsample was crystallized from methanol.

m.p.=247° C. (dec.); MS(m/e): 349(M⁺); Calculated for C₂₀ H₂₃ N₅ O:Theory: C, 68.74; H, 6.63; N, 20.04. Found: C, 68.96; H, 6.68; N, 20.07.

EXAMPLE 129 N- 4-fluorophenyl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!urea

Beginning with 0.15 gm (0.65 mmol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.096 mL(0.85 mMol) 4-fluorophenyl isocyanate, 0.176 gm (74%) of the titlecompound were recovered essentially by the procedure of Example 122. Ananalytical sample was crystallized from methanol.

m.p.=245.8° C. (dec.); MS(m/e): 367(M⁺); Calculated for C₂₀ H₂₂ N₅ OF:Theory: C, 65.38; H, 6.03; N, 19.06. Found: C, 65.36; H, 6.23; N, 18.91.

EXAMPLE 130 N- ethyl!-N'- 3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridin-5-yl!thiourea

Beginning with 0.15 gm (0.65 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.068 mL(0.78 mMol) ethyl isothiocyanate, 0.032 gm (10%) of the title compoundwere recovered essentially by the procedure of Example 122. Ananalytical sample was crystallized from aqueous ethanol.

MS(m/e): 317(M⁺)

EXAMPLE 131 5-(N-ethoxycarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.005 mL(0.053 mMol) ethyl chloroformate, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 303(M+1)

EXAMPLE 132 5-(N-isobutoxycarbonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo3,2-b!pyridine

Beginning with 0.010 gm (0.044 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.007 mL(0.053 mMol) isobutyl chloroformate, the title compound was preparedessentially by the procedure described in Example 7.

MS(m/e): 331(M+1)

EXAMPLE 133 5-(N-prop-1-en-3-yloxycarbonyl!amino)-3-(piperidin-4-yl)pyrrolo3,2-b!pyridine

A mixture of 4.0 gm (12.6 mMol)5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo 3,2-b!pyridineand 2.7 mL (25.2 mMol) allyl chloroformate in 200 mL pyridine was heatedat 50° C. for 5 hours. At this point an additional 2 mL of allylchloroformate were added and heating was continued for another 1.5hours. The reaction mixture was concentrated under reduced pressure andthe resulting residue partitioned between 1N sodium hydroxide andchloroform. The phases were separated and the aqueous phase wasextracted well with chloroform. The organic phases were combined, washedwith saturated aqueous sodium chloride, dried over sodium sulfate andconcentrated under reduced pressure. This residue was dissolved in 2Mammonia in methanol for two hours. The reaction mixture was concentratedunder reduced pressure and the residue subjected to flash silica gelchromatography, eluting with dichloromethane containing from 2-5%methanol and 1% ammonium hydroxide. Fractions containing product werecombined and concentrated under reduced pressure. The residue wascrystallized from aqueous ethanol to provide 2.9 gm (60%) 5-(N-prop-1-en-3-yloxycarbonyl!amino)-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo3,2-b!pyridine.

MS(m/e): 400(M⁺); Calculated for C₂₁ H₂₈ N₄ O₄ : Theory: C, 62.98; H,7.05; N, 13.99. Found: C, 63.06; H, 7.20; N, 14.11.

Deprotection

A solution of 0.75 gm (1.87 mMol) 5-(N-prop-1-en-3-yloxycarbonyl!amino)-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo3,2-b!pyridine in 5 mL dichloromethane was cooled to 0° C. To thissolution were then added 5 mL trifluoroacetic acid and the reactionmixture was allowed to warm gradually to room temperature. After 2 hoursthe reaction mixture was concentrated under reduced pressure to provide0.53 gm (95%) of the title compound as a white solid.

EXAMPLE 134 5-(N-phenylsulfonyl!amino)-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine

Beginning with 0.40 gm (1.74 mMol)5-amino-3-(1-methylpiperidin-4-yl)pyrrolo 3,2-b!pyridine and 0.267 mL(2.09 mMol) phenylsulfonyl chloride, 0.493 gm (76%) of the titlecompound were prepared as an orange solid essentially by the proceduredescribed in Example 4. An analytical sample was crystallized fromaqueous ethanol.

m.p. =148.1-149.7° C.; MS(m/e): 371(M+1); Calculated for C₁₉ H₂₂ N₄ O₂S: Theory: C, 61.60; H, 5.99; N, 15.12. Found: C, 61.87; H, 6.26; N,15.29.

The ability of the compounds of this invention to bind to the 5-HT_(1F)receptor subtype was measured essentially as described in U.S. Pat. No.5,521,196.

Membrane Preparation

Membranes were prepared from transfected Ltk- cells which were grown to100% confluency. The cells were washed twice with phosphate-bufferedsaline, scraped from the culture dishes into 5 mL of ice-coldphosphate-buffered saline, and centrifuged at 200×g for 5 minutes at 4°C. The pellet was resuspended in 2.5 mL of ice-cold Tris buffer (20 mMTris HCl, pH=7.4 at 23° C. mM EDTA) and homogenized with a Wheatontissue grinder. The lysate was subsequently centrifuged at 200×g for 5minutes at 4° C. to pellet large fragments which were discarded. Thesupernatant was collected and centrifuged at 40,000×g for 20 minutes at4° C. The pellet resulting from this centrifugation was washed once inice-cold Tris wash buffer and resuspended in a final buffer containing50 mM Tris HCl and 0.5 mM EDTA, pH=7.4 at 23° C. Membrane preparationswere kept on ice and utilized within two hours for the radioligandbinding assays. Protein concentrations were determined by the method ofBradford (Anal. Biochem., 72, 248-254 (1976)).

Radioligand Binding

³ H-5-HT! binding was performed using slight modifications of the5-HT_(1D) assay conditions reported by Herrick-Davis and Titeler (J.Neurochem., 50, 1624-1631 (1988)) with the omission of masking ligands.Radioligand binding studies were achieved at 37° C. in a total volume of250 μL of buffer (50 mM Tris, 10 mM MgCl₂, 0.2 mM EDTA, 10 μM pargyline,0.1% ascorbate, pH=7.4 at 37° C.) in 96 well microtiter plates.Saturation studies were conducted using ³ H!5-HT at 12 differentconcentrations ranging from 0.5 nM to 100 nM. Displacement studies wereperformed using 4.5-5.5 nM ³ H!5-HT. The binding profile of drugs incompetition experiments was accomplished using 6-12 concentrations ofcompound. Incubation times were 30 minutes for both saturation anddisplacement studies based upon initial investigations which determinedequilibrium binding conditions. Nonspecific binding was defined in thepresence of 10 μM 5-HT. Binding was initiated by the addition of 50 μLmembrane homogenates (10-20 μg). The reaction was terminated by rapidfiltration through presoaked (0.5% poylethyleneimine) filters using 48RCell Brandel Harvester (Gaithersburg, Md.). Subsequently, filters werewashed for 5 seconds with ice cold buffer (50 mM Tris HCl, pH=7.4 at 40°C.), dried and placed into vials containing 2.5 mL Readi-Safe (Beckman,Fullerton, Calif.) and radioactivity was measured using a Beckman LS5000TA liquid scintillation counter. The efficiency of counting of ³H!5-HT averaged between 45-50%. Binding data was analyzed bycomputer-assisted nonlinear regression analysis (Accufit and Accucomp,Lunden Software, Chagrin Falls, Ohio). IC₅₀ values were converted toK_(i) values using the Cheng-Prusoff equation (Biochem. Pharmacol., 22,3099-3108 (1973). All experiments were performed in triplicate.

Representative compounds of this invention were found to have affinityfor the 5-HT_(1F) receptor as measured by the procedure described supra.

As was reported by R. L. Weinshank, et al., WO93/14201, the 5-HT_(1F)receptor is functionally coupled to a G-protein as measured by theability of serotonin and serotonergic drugs to inhibit forskolinstimulated cAMP production in NIH3T3 cells transfected with the5-HT_(1F) receptor. Agonist activation of G-protein-coupled receptorsalso results in the release of CDP from the α-subunit of the G proteinand the subsequent binding of GTP. The binding of the stable analog ³⁵S!GTPγS is an indicator of this receptor activation.

Membrane Preparation

Mouse LM(tk-)cells stably transfected with the human 5-HT_(1F) receptorand grown in suspension were harvested by centrifugation, resuspended in50 mM Tris-HCl, pH 7.4, in aliquots of 2×10⁸ cells and frozen at -70° C.until the day of the assay. On the assay day, an aliquot of cells wasthawed, resuspended in 35 mL of 50 mM Tris-HCl, pH 7.4, and centrifugedat 39,800×g for 10 minutes at 4° C. The resulting pellet was resuspendedin 50 mM Tris-HCl, pH 7.4, incubated for 10 minutes at 37° C. andcentrifuged at 39,800×g for 10 minutes at 4° C. The pellet wasresuspended and centrifuged once more, with the final pellet beingresuspended in 4 mM MgCl₂, 160 mM NaCl, 0.267 mM EGTA, 67 mM Tris-HCl,pH 7.4, such that a 200 μL aliquot contained contained approximately15-25 μg protein.

³⁵ S!GTPγS binding

All incubations were performed intriplicate in a total volume of 800 μL.Drug dilution in water, 200 μL, spanning 6 log units, was added to 400μL of Tris-HCl, pH 7.4, containing 3 mM MgCl₂, 120 mM NaCl, 0.2 mM EGTA,10 μM GDP, and 0.1 nM ³⁵ S!GTPγS. Membrane homogenate, 200 μL, was addedand then the tubes were incubated for 30 minutes at 37° C. Using aBrandel cell harvester (model MB-48R, Brandel, Gaithersburg, Md.), theincubations were then terminated by vacuum filtration through WhatmanGF/B filters which had been wet with water or 20 mM Na₄ P₂ O₇ andprecooled with 4 mL of ice-cold 50 mM Tris-HCl, pH 7.4. The filters werethen washed rapidly with 4 mL of ice-cold 50 mM Tris-HCl, pH 7.4. Theamount of radioactivity captured on the filters was determined by liquidscintillation spectrometry using an LS6000IC (Beckman Instruments,Fullerton, Calif.). GTPγS, 10 μM, defined nonspecific binding. Proteinwas determined by the method of Bradford (Anal. Biochem., 72, 248-254(1976)).

Statistical Analysis

Efficacy values for test compounds were expressed as the percent bindingrelative to 10 μM 5-HT. Nonlinear regression analysis was performed onthe concentration response curves using a four parameter logisticequation described by De Lean et al., (Mol. Pharamacol., 21, 5-16(1982)). Analysis of variance, followed by the Tukey-Kramer HonestlySignificant Difference test (JMP; SAS Institute Inc., Cary, N.C.) wasperformed on the pEC₅₀ values and the E_(max) values.

Representative compounds of the present invention were tested in the ³⁵S!GTPγS assay and were found to be agonists of the 5-HT_(1F) receptor.

The discovery that the pain associated with migraine and associateddisorders is inhibited by activation of the 5-HT_(1F) receptor byadministration of 5-HT_(1F) agonists required the analysis of data fromdiverse assays of pharmacological activity. To establish that the5-HT_(1F) receptor subtype is responsible for mediating neurogenicmeningeal extravasation which leads to the pain of migraine, the bindingaffinity of a panel of compounds to serotonin receptors was measuredfirst, using standard procedures. For example, the ability of a compoundto bind to the 5-HT_(1F) receptor subtype was performed as describedsupra. For comparison purposes, the binding affinities of compounds tothe 5-HT_(1D)α, 5-HT_(1D)β, and 5-HT_(1E) receptors were also determinedas described supra, except that different cloned receptors were employedin place of the 5-HT_(1F) receptor clone employed therein. The samepanel was then tested in the cAMP assay to determine their agonist orantagonist character. Finally, the ability of these compounds to inhibitneuronal protein extravasation, a functional assay for migraine pain,was measured.

The panel of compounds used in this study represents distinct structuralclasses of compounds which were shown to exhibit a wide range ofaffinities for the serotonin receptors assayed. Additionally, the panelcompounds were shown to have a wide efficacy range in the neuronalprotein extravasation assay as well. The panel of compounds selected forthis study are described below.

Compound I

3- 2-(dimethylamino)ethyl!-N-methyl-1H-indole-5-methanesulfonamidebutane-1,4-dioate (1:1) (Sumatriptan succinate) ##STR8##

Sumatriptan succinate is commercially available as Imitrex™ or may beprepared as described in U.S. Pat. No. 5,037,845, issued Aug. 6, 1991,which is herein incorporated by reference in its entirety.

Compound II

5-fluoro-3-(1-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-4-piperidinyl)-1H-indolehydrochloride ##STR9##

Compound III

5-hydroxy-3-(4-piperidinyl)-1H-indole oxalate ##STR10##

Compound IV

8 -chloro-2-diethylamino-1,2,3,4-tetrahydronaphthalene hydrochloride##STR11##

Compound V

6-hydroxy-3-dimethylamino-1,2,3,4-tetrahydrocarbazole ##STR12##

The preparation of Compounds II-V are described in U.S. Pat. No.5,521,196, issued May 28, 1996, which is herein incorporated byreference in its entirety.

Binding Assays

The binding affinities of compounds for various serotonin receptors weredetermined essentially as described above except that different clonedreceptors are employed in place of the 5-HT_(1F) receptor clone employedtherein. The results of these binding experiments are summarized inTable I.

                  TABLE I    ______________________________________    BINDING TO SEROTONIN (5-HT.sub.1) RECEPTOR SUBTYPES    (K.sub.i nM) cAMP Formation    As was reported by R. L. Weinshank, et al., WO93/14201,    the 5-HT.sub.1F receptor is functionally coupled to a G-protein as    measured by the ability of serotonin and serotonergic drugs to    inhibit forskolin stimulated cAMP production in NIH3T3 cells    transfected with the 5-HT.sub.1F receptor. Adenylate cyclase    activity was determined using standard techniques. A maximal    effect is achieved by serotonin. An E.sub.max is determined by    dividing the inhibition of a test compound by the maximal    effect and determining a percent inhibition. (N. Adham, et    al., supra,; R. L. Weinshank, et al., Proceedings of the    National Academy of Sciences (USA), 89, 3630-3634 (1992)), and    the references cited therein.    Compound   5-HT.sub.1Dα                        5-HT.sub.1Dβ                                   5-HT.sub.1E                                         5-HT.sub.1F    ______________________________________    I          4.8      9.6        2520.0                                         25.7    II         21.7     53.6       50.3  2.5    III        163.2    196.5      3.9   22.0    IV         13.5     145.3      813.0 129.2    V          791.0    1683.0     73.6  10.3    ______________________________________

Measurement of cAMP formation

Transfected NIH3T3 cells (estimated Bmax from one point competitionstudies=488 fmol/mg of protein) were incubated in DMEM, 5 mMtheophylline, 10 mM HEPES (4- 2-hydroxyethyl!-1-piperazineethanesulfonicacid) and 10 μM pargyline for 20 minutes at 37° C., 5% CO₂. Drugdose-effect curves were then conducted by adding 6 different finalconcentrations of drug, followed immediately by the addition offorskolin (10 μM). Subsequently, the cells were incubated for anadditional 10 minutes at 37° C., 5% CO₂. The medium was aspirated andthe reaction was stopped by the addition of 100 mM HCl. To demonstratecompetitive antagonism, a dose-response curve for 5-HT was measured inparallel, using a fixed dose of methiothepin (0.32 μM). The plates werestored at 4° C. for 15 minutes and then centrifuged for 5 minutes at500×g to pellet cellular debris, and the supernatant was aliquoted andstored at -20° C. before assessment of cAMP formation byradioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics,Cambridge, Mass.). Radioactivity was quantified using a Packard COBRAAuto Gamma counter, equipped with data reduction software.

All of the compounds of the panel were tested in the cAMP formationassay described supra and all were found to be agonists of the 5-HT_(1F)receptor.

Protein Extravasation

Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles RiverLaboratories (225-325 g) were anesthetized with sodium pentobarbitalintraperitoneally (65 mg/kg or 45 mg/kg respectively) and placed in astereotaxic frame (David Kopf Instruments) with the incisor bar set at-3.5 mm for rats or -4.0 mm for guinea pigs. Following a midline sagitalscalp incision, two pairs of bilateral holes were drilled through theskull (6 mm posteriorly, 2.0 and 4.0 mm laterally in rats; 4 mmposteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinatesreferenced to bregma). Pairs of stainless steel stimulating electrodes(Rhodes Medical Systems, Inc.) were lowered through the holes in bothhemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) fromdura.

The femoral vein was exposed and a dose of the test compound wasinjected intravenously (1 mL/kg). Approximately 7 minutes later, a 50mg/kg dose of Evans Blue, a fluorescent dye, was also injectedintravenously. The Evans Blue complexed with proteins in the blood andfunctioned as a marker for protein extravasation. Exactly 10 minutespost-injection of the test compound, the left trigeminal ganglion wasstimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msecduration) with a Model 273 potentiostat/galvanostat (EG&G PrincetonApplied Research).

Fifteen minutes following stimulation, the animals were killed andexsanguinated with 20 mL of saline. The top of the skull was removed tofacilitate the collection of the dural membranes. The membrane sampleswere removed from both hemispheres, rinsed with water, and spread flaton microscopic slides. Once dried, the tissues were coverslipped with a70% glycerol/water solution.

A fluorescence microscope (Zeiss) equipped with a grating monochromatorand a spectrophotometer was used to quantify the amount of Evans Bluedye in each sample. An excitation wavelength of approximately 535 nm wasutilized and the emission intensity at 600 nm was determined. Themicroscope was equipped with a motorized stage and also interfaced witha personal computer. This facilitated the computer-controlled movementof the stage with fluorescence measurements at 25 points (500 μm steps)on each dural sample. The mean and standard deviation of themeasurements was determined by the computer.

The extravasation induced by the electrical stimulation of thetrigeminal ganglion was an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the other (unstimulated) half of the dura to be used as acontrol. The ratio of the amount of extravasation in the dura from thestimulated side compared to the unstimulated side dura was calculated.Saline controls yielded a ratio of approximately 2.0 in rats and 1.8 inguinea pigs. In contrast, a compound which effectively prevented theextravasation in the dura from the stimulated side would have a ratio ofapproximately 1.0. A dose-response curve was generated and the dose thatinhibited the extravasation by 50% (ID₅₀) was approximated. This data ispresented in Table II.

                  TABLE II    ______________________________________    Inhibition of Protein Extravasation (ID.sub.50 mMol/kg)                         i.v. ID.sub.50    Compound             (mMol/kg)    ______________________________________    I                    2.6 × 10.sup.-8    II                   8.6 × 10.sup.-10    III                  8.9 × 10.sup.-9    IV                   1.2 × 10.sup.-7    V                    8.7 × 10.sup.-9    ______________________________________

To determine the relationship of binding at various serotonin receptorsto inhibition of neuronal protein extravasation, the binding affinity ofall of the compounds to each of the 5-HT_(1D)α, 5-HT_(1D)β, 5-HT_(1E)and 5-HT_(1F) receptors was plotted against their ID₅₀ in the proteinextravasation model. A linear regression analysis was performed on eachset of data and a correlation factor, R², calculated. The results ofthis analysis are summarized in Table III.

                  TABLE III    ______________________________________    Correlation Factor (R.sup.2) for Specific 5-HT.sub.1 Subtype Binding    Affinity vs Inhibition of Protein Extravasation    5-HT.sub.1 Subtype                  Correlation Factor (R.sup.2)    ______________________________________    5-HT.sub.1Dα                  0.07    5-HT.sub.1Dβ                  0.001    5-HT.sub.1E   0.31    5-HT.sub.1F   0.94    ______________________________________

An ideally linear relationship would generate a correlation factor of1.0, indicating a cause and effect relationship between the twovariables. The experimentally determined correlation factor betweeninhibition of neuronal protein extravasation and 5-HT_(1F) bindingaffinity is 0.94. This nearly ideal dependence of the ID₅₀ in theprotein extravasation model on binding affinity to the 5-HT_(1F)receptor clearly demonstrates that the 5-HT_(1F) receptor mediates theinhibition of protein extravasation resulting from stimulation of thetrigeminal ganglia.

Sumatriptan exhibits low bioavailability and relatively short durationof action. Its affinity for a number of serotonin receptor subtypesgives rise to undesirable side effects, particularly vasoconstriction,which severely limits its utility in the treatment of migraine. Thecompounds of this invention, however, are highly bioavailable throughseveral routes of administration including, but not limited to, oral,buccal, intravenous, subcutaneous, intranasal, intraocular, transdermal,rectal and by inhalation. They exhibit a rapid onset and long durationof action, typically requiring only a single dose per day to maintaintherapeutic levels. Since compounds of this invention are potentagonists of the 5-HT_(1F) receptor, extremely low doses are required tomaintain therapeutic levels. Additionally, due to the high selectivityof compounds of this invention for the 5-HT_(1F) receptor, complicationsdue to vasoconstriction are avoided. Compounds of this invention alsoinhibit protein extravasation if administered prior or subsequent tostimulation of the trigeminal ganglia, suggesting they may beadministered prior to an incipient migraine attack to prevent pain, orduring a migraine attack to alleviate pain.

The ability of agonists of the 5-HT_(1F) receptor in general, and thecompounds of the present invention specifically, to alleviate pain isdemonstrated by testing in a standard model of chronic pain (Calvino, etal. Behavioural Brain Research, 24, 11-29 (1987); Colpaert, Pain, 28,201-222 (1987)). For example, an arthritis like state can be produced inrats days after a single injection of Freund's Complete Adjuvant or asynthetic adjuvant like lipoidal amine(N,N-dioctyldecyl-N',N-bis(2-hydroxyethyl) propanediamine) in oil(Benslay and Bendele, Agents Actions 34(1-2), 254-6, (1991); Bendele etal., J Pharmacol Exp Ther 260(1), 300-5 (1992); Meacock et al., AnnRheum Dis 53(10), 653-8 (1994)). Animals treated this way developchronically swollen and painful hindpaws resulting in increasedirritability, and decreased locomotion. The ideal analgesic wouldincrease the exploratory activity of arthritic animals toward normalwithout increasing or decreasing this behavior in normal animals.Analgesic compounds, for example morphine and citalopram, have beendemonstrated to improve exploratory behavior in these animals (Larsenand Arnt, Acta Pharmacol Toxicol (Copenh) 57(5), 345-51 (1985)).

Analgesic assay

Male Lewis rats (Harlan-Sprague Dawley, Inc., Indianapolis, Ind.)weighing about 225 grams are housed in clear plastic cages with ad libaccess to chow and water. Rats are maintained under a 12 hours on and 12hours off light cycle.

To produce polyarthritis, half of the rats are injected subcutaneouslyat the dorsal base of the tail with 7.5 mg/rat of lipoidal amine in 0.1ml of Incomplete Freund's Adjuvant. This single lipoidal amine injectionresults in hindpaw inflammation which becomes obvious in about ten days.The other half of the rats receive vehicle injections. Eleven days afterlipoidal amine or vehicle injection, animals are treated either orallyor subcutaneously with test compound or water vehicle. One hour aftertreatment, individual animals are placed in activity monitors (OmnitechElectronics, Columbus, Ohio) which constitute a novel environment. Theactivity monitors have an "open field" area of 42×42 cm and, usinginfrared light beams and photocells, quantify exploratory behavior. Thisis accomplished using a grid of photosensors placed at floor level tomeasure horizontal activity. A computer analyzes the data from thesensor array. Exploratory behavior is quantified during the first 5minutes in the chamber. The measured parameter used in this study istotal distance traveled during the 5 minute test period.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These compositions can be administered by a varietyof routes including oral, buccal, rectal, intranasal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Many of thecompounds employed in the methods of this invention are effective asboth injectable and oral compositions. Such compositions are prepared ina manner well known in the pharmaceutical art and comprise at least oneactive compound. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16thed. 1980).

In making the compositions employed in the present invention the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within such a carrier which can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.001 to about 100 mg, more usually about1.0 to about 30 mg, of the active ingredient. The term "unit dosageform" refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compounds are generally effective over a wide dosage range.For examples, dosages per day normally fall within the range of about0.0001 to about 30 mg/kg of body weight. In the treatment of adulthumans, the range of about 0.1 to about 15 mg/kg/day, in single ordivided dose, is especially preferred. However, it will be understoodthat the amount of the compound actually administered will be determinedby a physician, in the light of the relevant circumstances, includingthe condition to be treated, the chosen route of administration, theactual compound or compounds administered, the age, weight, and responseof the individual patient, and the severity of the patient's symptoms,and therefore the above dosage ranges are not intended to limit thescope of the invention in any way. In some instances dosage levels belowthe lower limit of the aforesaid range may be more than adequate, whilein other cases still larger doses may be employed without causing anyharmful side effect, provided that such larger doses are first dividedinto several smaller doses for administration throughout the day.

Formulation Example 1

Hard gelatin capsules containing the following ingredients are prepared:

    ______________________________________                      Quantity    Ingredient        (mg/capsule)    ______________________________________    Compound of Example 8                      30.0    Starch            305.0    Magnesium stearate                      5.0    ______________________________________

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

Formulation Example 2

A tablet formula is prepared using the ingredients below:

    ______________________________________                      Quantity    Ingredient        (mg/tablet)    ______________________________________    Compound of Example 2                      25.0    Cellulose, microcrystalline                      200.0    Colloidal silicon dioxide                      10.0    Stearic acid      5.0    ______________________________________

The components are blended and compressed to form tablets, each weighing240 mg.

Formulation Example 3

Suppositories, each containing 25 mg of active ingredient are made asfollows:

    ______________________________________    Ingredient          Amount    ______________________________________    Compound of Example 4                          25 mg    Saturated fatty acid glycerides to                        2,000 mg    ______________________________________

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 4

An intravenous formulation may be prepared as follows:

    ______________________________________    Ingredient             Quantity    ______________________________________    Compound of Example 19 250.0 mg    Isotonic saline         1000 ml    ______________________________________

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices ("patches"). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which isherein incorporated by reference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

The type of formulation employed for the administration of the compoundsemployed in the methods of the present invention may be dictated by theparticular compounds employed, the type of pharmacokinetic profiledesired from the route of administration and the compound(s), and thestate of the patient.

We claim:
 1. The compound of Formula III: ##STR13##